* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 1970, vol. 35, p. 2746 - 2750
2
[ 1878-67-7 ]
[ 74-88-4 ]
[ 53086-52-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.25 h; Stage #2: at -78 - 20℃;
A solution of LDA in THF/n-heptane/ethylbenzene (1.8M, 23.25 mL, 41.85 mmol) is cooled down to -78°C and added a solution of 3-bromophenylacetic acid [3 g, 13.95 mmol, Intermediate (68)] in THF (7 mL) dropwise over 15 minutes. The mixture is stirred for 1 h at -78°C and treated dropwise with methyl iodide (6.34 g, 44.64 mmol) over 15 minutes. The reaction mixture is warmed up to room temperature and after stirring overnight, the mixture is quenched with 2N hydrochloric acid and concentrated to remove THF. The residue is diluted with ether, washed twice with 2 N hydrochloric acid (20 mL) and extracted twice with 10percent sodium hydroxide (20 mL). The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (50 mL). Combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 2-f3-bromo-phenyl)-propionic acid [3 g, 100percent, Intermediate (69)] as a solid, which is used without further purification. LC/MS: 229 (M+H).
100%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.25 h; Stage #2: at -78 - 20℃;
A solution of LDA in THF/n-heptane/ethylbenzene (1.8M, 23.25 mL, 41.85 mmol) is cooled down to -78°C and added a solution of 3-bromophenylacetic acid [3 g, 13.95 mmol, Intermediate (68)] in THF (7 mL) dropwise over 15 minutes. The mixture is stirred for 1 h at -78°C and treated dropwise with methyl iodide (6.34 g, 44.64 mmol) over 15 minutes. The reaction mixture is warmed up to room temperature and after stirring overnight, the mixture is quenched with 2N hydrochloric acid and concentrated to remove THF. The residue is diluted with ether, washed twice with 2 N hydrochloric acid (20 mL) and extracted twice with 10percent sodium hydroxide (20 mL). The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (50 mL). Combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 2-f3-bromo-phenyl)-propionic acid [3 g, 100percent, Intermediate (69)] as a solid, which is used without further purification. LC/MS: 229 (M+H).
84%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at 20℃; for 0.25 h; Stage #2: at 20℃; for 0.25 h; Stage #3: at 20℃; for 0.25 h;
To a solution of diisopropylamine (0.97 g, 9.6 mmol) in THF (20 mL) at room temperature was added n-butyl lithium (2.5 N in hexane, 4 mL, 10 mmol) and the resulting solution was stirred at room temperature for 15 minutes. To above solution was added a solution of 3-bromophenylacetic acid (1.0 g, 4.6 mmol) in THF (10 mL) dropwise at room temperature and the stirring was continued for another 15 minutes. Methyl iodide (1.49 g, 10.5 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. Satuated sodium chloride (30 mL) was added and the aqueous phase was adjusted to pH 5 by addition of hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (20 mL.x.3) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of formic acid and methanol in dichloromethane to afford 2-(3-bromo-phenyl)-propionic acid (890 mg, 84percent) as a white solid. MS: m/z 229 (M+H+).
82%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran; toluene at 20℃; for 0.333333 h; Stage #2: for 0.166667 h;
General procedure: Step 1. To a solution of 3-bromophenylacetic acid (1.30 g, 6 mmol) (azeotroped with toluene) in 2 mL of dry toluene was added sodium bis(trimethylsilyl)amide (14 mL of 1N solution in THF, 14 mmol). After stirring at room temperature for 20 min, methyl iodide (0.9 g, 7 mmol) was added dropwise. After 10 min, the reaction was quenched with 2 N HCl to pH = 2, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to dryness. Flash column (SiO2, DCM to DCM/EtOAc = 10:1 to 4:1 to 2:1) gave crude 2-(3-bromophenyl)propanoic acid (1.13 g, 82percent yield) as colorless oil.
Stage #1: With C28H22CoN4O6 In butan-1-ol at 60℃; for 2 h; Glovebox; High pressure; Green chemistry Stage #2: With tetra-(n-butyl)ammonium iodide; sodium hydroxide In butan-1-ol at 60℃; for 22 h; Glovebox; High pressure; Green chemistry
General procedure: A 100 mL reactor equipped with Teflon-coated magnetic stir bars was charged with n-Butyl alcohol (20 mL) and the catalyst (0.5 mmol). The reactor was then taken out of the glove box and pressured with carbon monoxide (1 atm). The mixture was stirred 2 h at 60 °C, cooled to ambient temperature and slowly vented. After benzyl chloride (10 mmol), NaOH (15 mL, 15percent), and TBAI (0.25 mmol) were added, the reactor was sealed and the reaction mixtures were stirred for 22 h at 60 °C under carbon monoxide (1 atm). After the reaction, the water phase was detached and washing the organic phase three times with H2O (3×5 mL), the combined water layer was washed with Et2O, then the resulting solution was cooled to 0 °C and adjusted to pH=1–2 with HCl (6 mol/L). The product was filtered, dried in RT, and then recrystallized.
Stage #1: for 14 h; Reflux Stage #2: With sulfuric acid; acetic acid In water at 20 - 30℃; for 6 h; Reflux
In 1000ml three-necked flask of sublimed sulfur were added 24g (0.75mol), 100g3- bromoacetophenone (0.5mol) and 65.4g (0.75mol) morpholine was stirred at reflux for 14 hours. Cooling to 20 ~ 30 , stirring joined by glacial acetic acid 260ml, 75ml and 52ml distilled water mixed with concentrated sulfuric acid solution dubbed refluxing was continued for 6 hours. The reaction mixture was poured into ice water, stirring to brown solid precipitated was filtered. The solid was dissolved 300ml20percent aqueous sodium hydroxide solution and filtered. The filtrate was placed in an ice bath, 2mol / L of hydrochloric acid to adjust pH = 1 ~ 2, crystallization, filtration, 60 dried to give 99.2g of yellow solid 2, a yield of 92.3percent.
Reference：
[1] Patent: CN105348195, 2016, A, . Location in patent: Paragraph 0005; 0015
5
[ 31938-07-5 ]
[ 1878-67-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3018 - 3022
[2] Journal fuer Praktische Chemie (Leipzig), 1932, vol. <2> 133, p. 331,346
[3] Journal of the Chemical Society, 1948, p. 1251,1254
[4] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1880, p. 481
6
[ 14062-30-7 ]
[ 1878-67-7 ]
Yield
Reaction Conditions
Operation in experiment
4.1 g
With lithium hydroxide In tetrahydrofuran; water at 20℃; for 1 h;
Under room temperature, will ethyl 3-bromophenylacetate (5.0 g, 20.6 mmol) and LiOH (1.0 g, 41.8 mmol) added THF (30 ml) and water (20 ml) in the mixed solution. Under room temperature, the resultant reaction mixture of 1 hour. Using 2N pH=2. HCl solution to adjust the The resulting mixture is extracted with ethyl acetate. The resulting organic phase is concentrated to obtain 4.1 g of white solid.
Reference：
[1] Patent: CN105384739, 2016, A, . Location in patent: Paragraph 0312; 0313; 0314
7
[ 124-38-9 ]
[ 306773-37-5 ]
[ 1878-67-7 ]
Reference：
[1] Chemical Science, 2018, vol. 9, # 21, p. 4873 - 4878
8
[ 2039-86-3 ]
[ 1878-67-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 12, p. 2132 - 2141
[2] RSC Advances, 2016, vol. 6, # 8, p. 6719 - 6723
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 3, p. 183 - 188
20
[ 1878-67-7 ]
[ 14062-25-0 ]
[ 14062-30-7 ]
Reference：
[1] Patent: US5489584, 1996, A,
21
[ 1878-67-7 ]
[ 2084-13-1 ]
Reference：
[1] Patent: WO2013/52110, 2013, A1,
22
[ 1878-67-7 ]
[ 28229-69-8 ]
Yield
Reaction Conditions
Operation in experiment
79%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 20 h; Stage #2: With water In tetrahydrofuran
BH3-Me2S (7 ml_ of a 2M solution in THF, 14.0 mmol) was added to a cold (0 0C) solution of 3-bromophenylacetic acid (2.00 g, 9.3 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 20 hours and re-cooled to 0 0C. Water (10 ml.) was added dropwise. The organic layer was separated, washed with brine (20 mL), dried (MgSO4), filtered and concentrated under reduced pressure to leave a colourless oil. Purification by column chromatography (50 percent EtOAc in heptane) afforded the title compound as a colourless oil (1.47 g, 79 percent yield). m/z 224/226 [M+H]+. 1H NMR (300 MHz, CDCI3) 7.41-7.35 (2H, m), 7.23-7.16 (2H, m), 3.87 (2H, t, J=6.5 Hz), 2.86 (2H, t, J=6.5 Hz).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3018 - 3022
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 3, p. 183 - 188
[3] Patent: WO2008/53136, 2008, A1, . Location in patent: Page/Page column 38
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2882 - 2891
[5] Journal of Medicinal Chemistry, 1998, vol. 41, # 3, p. 358 - 378
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 5, p. 1562 - 1575
[7] Patent: WO2006/11631, 2006, A2, . Location in patent: Page/Page column 67-68
[8] Patent: US6316466, 2001, B1,
[9] Patent: US5827868, 1998, A,
[10] Patent: US5087635, 1992, A,
[11] Patent: WO2004/67521, 2004, A1, . Location in patent: Page 228-229
[12] Journal of the American Chemical Society, 2010, vol. 132, # 12, p. 4076 - 4077
[13] Patent: WO2007/69986, 2007, A1, . Location in patent: Page/Page column 89
[14] Journal of the American Chemical Society, 2011, vol. 133, # 43, p. 17142 - 17145
[15] Patent: US2014/57914, 2014, A1, . Location in patent: Paragraph 0356-0357
[16] Chemistry - A European Journal, 2014, vol. 20, # 47, p. 15325 - 15329
[17] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
23
[ 1878-67-7 ]
[ 14062-30-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
With sulfuric acid In ethanolReflux
Step A: Ethyl 2-(3-bromophenyl acetate (35i-b) 3-Bromophenylacetic acid, 35i-a, (50g, 0.23mol) was dissolved in ethanol (250 mL) and sulfuric acid was added drop-wise. The mixture was heated to reflux and stirred overnight. The solution was adjusted to about a pH of 7-8 with sodium hydroxide solution and concentrated in vacuo. The water phase was extracted with ethyl atetate (3 x 150 mL) and the combined organics was washed with brine (50 mL) and dried, concentrated to give the compound, 35i-b, (52.6g, 93percent) as colorless oil. NMR (300 MHz, CDCI3) δ 1.24-1.29 (m, 3H), 3.58 (s, 2H), 4.1 1-4.19 (m, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 2H). LC-MS (M+H)+ 243, 245.
Preparation of ethyl 3-bromophenylacetate: 2.5 ml of conc. sulphuric acid were added to a solution of 25 g (116 mmol) of 3-bromophenylacetic acid in 170 ml of ethanol. The mixture was heated under reflux for 20 h. After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in 800 ml of ethyl acetate. The organic phase was washed three times with in each case 50 ml of saturated aqueous sodium bicarbonate solution and twice with in each case 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and, after filtration, concentrated under reduced pressure. The residue obtained in this manner was purified by column chromatography on silica gel using the mobile phase hexane/0-20percent ethyl acetate. This gave 27.8 g (98percent of theory) of ethyl 3-bromophenylacetate. Preparation of the Title Compound:
97%
at 0℃; for 2 h; Reflux
Into a 250-mL round-bottom flask, were placed 2-(3-bromophenyl)acetic acid (5 g, 23.25mmol, 1 .00 equiv), ethanol (80m l_). This was followed by the addition of thionyl chloride (5.6 g, 46.28mmol, 2.00 equiv) dropwise with stirring at 0°C. The resulting solution was heated to reflux for 2 h. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated. This resulted in 5.5 g (97percent) of ethyl 2-(3-bromophenyl)acetate as colorless oil.
95%
at 80℃;
Compound I: Synthesis using modified procedure of Sonogashira: Step i: To a solution/suspension of 3-bromophenylacetic acid (5.02g, 23.33 mmol) in ethanol (100 ml.) at room temperature was added concentrated sulfuric acid (1mL). The colorless solid was then stirred overnight at 8O0C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with 2 x ethyl acetate (25 mL) and brine (20 mL). The combinated organic layers were washed with 2 x saturated solution of NaHCO3 (25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCI3): δ 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H)1 7.44 (d, J = 1.56 Hz, 1 H).
95%
at 80℃;
Example 1: Detailed experimental procedures for the preparation of the sodium salt of 3-pentylphenylacetic acid (hereinafter Compound I)Instrumentation:[00108] All HPLC chromatograms and mass spectra were recorded on an HP 1100 LC-MS Agilent instrument using an analytical C18 column (250 x 4.6 mm, 5 microns) with a gradient over 5 min of 15-99percent CH3CN-H2O with 0.01percent TFA as the eluant and a flow of 2 mL/min.Compound I: Synthesis using modified procedure of Sonogashira:Step i:[00109] To a solution/suspension of 3-bromophenylacetic acid (5.02g, 23.33 mmol) in ethanol (100 ml_) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solid was then stirred overnight at 8O0C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 ml_), water (25 mL) and the two layers were separated. The aqueous layer was extracted with 2 x ethyl acetate (25 mL) and brine (20 mL). The combinated organic layers were washed with 2 x saturated solution of NaHCO3 (25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCI3): δ 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H), 7.44 (d, J = 1.56 Hz, 1H).
95%
at 20 - 80℃;
[0088] Step 1 : To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol (100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solution was then stirred overnight at 80°C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2 χ 25 mL) and brine (20 mL). The combinated organic layers were washed with saturated solution of NaHC03 (2 χ 25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCI3): δ 1.26 (t J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1 H), 7.44 (d, J = 1.56 Hz, 1 H).
95%
at 80℃;
[00100] To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol(100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solidwas then stirred overnight at 80°C. The solution was concentrated under reduced pressure. Theresidue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated.The aqueous layer was extracted with ethyl acetate (2 x 25 mL) and brine (20 mL). Thecombinated organic layers were washed with saturated solution of NaHCO3 (2 x 25 mL), brine(25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness.This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCI3): ö 1.26 (t, J = 4.7 Hz, 3H),3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H), 7.44 (d, J =1.56 Hz, IH).
95%
at 80℃;
To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol (100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solid was then stirred overnight at 80°C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2 χ 25 mL) and brine (20 mL). The combinated organic layers were washed with saturated solution of NaHC03 (2 x 25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95percent). 1H-NMR (400 MHz, CDCIa): δ 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1 H), 7.44 (d, J = 1.56 Hz, 1 H).
93.4%
at 0 - 20℃; for 5.08333 h;
74 lStep 1. HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at O0C for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford (3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4percent] as an oil, which is used without further purification.
93.4%
at 0 - 20℃; for 5.08333 h;
HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at O0C for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford f3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4percent] as an oil, which is used without further purification.
93%
Reflux
3-Bromophenylacetic acid, 35i-a, (50g, 0.23mol) was dissolved in ethanol (250 mL) and sulfuric acid was added drop-wise. The mixture was heated to reflux and stirred overnight. The solution was adjusted to about a pH of 7-8 with sodium hydroxide solution and concentrated in vacuo. The water phase was extracted with ethyl atetate (3 x 150 mL) and the combined organics was washed with brine (50 mL) and dried, concentrated to give the compound, 35i-b, (52.6g, 93percent) as colorless oil. 1H NMR (300 MHz, CDCI3) δ 1.24-1.29 (m, 3H), 3.58 (s, 2H), 4.11-4.19 (m, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 2H). LC-MS (M+H)+243, 245
93.4%
at 0 - 20℃; for 5.08333 h;
HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at O0C for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford f3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4percent] as an oil, which is used without further purification.
88%
at 0 - 85℃;
Example A6; N-[(1-[3-[8-methyl-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl]phenyl]-1-methylethyl]amine; A6.1 tert-butyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamate; A6.1a: Ethyl 2-(3-bromophenyl)acetate; Commercially available 2-(3-bromophenyl)acetic acid (13 g 0.06 mol) was dissolved in ethanol (130 ml) and cooled to 0° C. Thionyl chloride (20 ml) was added drop wise. The mixture was heated to 85° C. over night. Reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10percent NaHCO3, water, dried over anhydrous sodium sulfate and concentrated to give 13 g (88percent) of A6.1a.
88%
at 20 - 80℃; for 15 h;
To an ice cooled solution of 2-(3-bromophenyl)acetic acid (1 g, 4.6 mmol) in EtOH (10 mL), thionyl chloride (0.67 mL, 9.3 mmol) was added dropwise. The reaction mixture was then warmed to room temperature heated at 80° C. for 15 h. The reaction was monitored by TLC and after completion of the reaction, the reaction mixture was concentrated under vacuo and water was added to the residue. A saturated aqueous solution of NaHCO3 was added to the solution until the pH of the solution was 9. Then, the aqueous solution was extracted with EtOAc, the organic layer was dried over Na2SO4, concentrated under vacuum, and purified by column chromatography (silica gel) to yield ethyl 2-(3-bromophenyl)acetate yield 1.13 g. (88percent).
11.1 g
for 3 h; Reflux
To a solution of 2-(3-bromophenyl)acetic acid 1103 (10.0 g, 46.5 mmol) in 100 mL EtOH was added cone. H2S04 (10 drops) and the mixture heated to relux temperature for 3 hours. The mixture was allowed to cool to room temperature and the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with water (2 x 50 mL), saturated NaHC03 (1 x 25 mL), brine (2 x 25 mL) and dried over Na2S04. The Na2S04 was removed by filtration and the volatiles removed under reduced pressure to give ethyl 2-(3-bromophenyl)acetate 1097 (11.1 grams) as a liquid). 1H NMR 300 MHz CDC13: δ 7.41 (m, 2 H), 7.20 (m, 2H), 4.14 (q, 2H, J= 9.5 Hz), 3.57 (s, 2H), 1.25 (t, 3H, J= 9.5 Hz).
Reference：
[1] Green Chemistry, 2017, vol. 19, # 20, p. 4798 - 4803
31
[ 67-56-1 ]
[ 1878-67-7 ]
[ 150529-73-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;
To dichloromethane (580 ml) solution of 25 g (116 mmol) of 3-bromophenylacetic acid were added 9.4 ml (232 mmol) of methanol and 0.15 g (1.2 mmol) of 4-(dimethylamino)pyridine. After cooling with ice, 26.8 g (140 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added thereto, and the resulting mixture was stirred overnight with gradually warming up to room temperature. The reaction mixture was washed with hydrochloric acid, saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. After filtrating and concentrating under reduced pressure, 27.3 g (quantitative) of the entitled compound was obtained as a pale yellow oil.1H-NMR(CDCl3)δ: 3.60(2H, s), 3.70(3H, s), 7.16-7.23(2H, m), 7.39-7.45(2H, m).
100%
Heating / reflux
A mixture of 3-bromophenylacetic acid (5.29 g, 24.6 mmol) and concentrated sulfuric acid (100 μL) in anhydrous methanol (40 mL) was refluxed overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo to give 121A (5.82 g, 100percent) as pale yellow oil. LC-MS m/z: 228.18 (M+H)+.
99%
for 2 h; Reflux
INTERMEDIATE 6(3-BromophenyDacetic acid methyl ester Acetyl chloride (0.5 niL) was added to MeOH (100 mL). 3-Bromophenylacetic acid (15 g, 69.8 mmol) was added, and the mixture refluxed for 2 h. The solvent was removed in vacuo and the residue partitioned between DCM and water (50 mL each). The aqueous phase was extracted with DCM (20 mL) and the combined organic phases were dried (MgSO4) and the solvent removed in vacuo to give the title compound (15.85 g, 99percent) as a colourless oil. δH (CDCl3) 7.44 (s, IH), 7.37-7.43 (m, IH), 7.15-7.24 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H).
98%
Heating / reflux
To a solution of 3-bromophenylacetic acid (1 g, 4.65 mmol) in 20 mL MeOH at 0° C. was added thionyl chloride (0.51 mL, 1.5 eq.) dropwise. The resulting solution was then refluxed overnight under N2. The reaction was cooled to rt and the solvent was removed in vacuo. The residue was taken up in EtOAc, washed with sat'd. NaHCO3 and brine, then dried over Na2SO4, filtered and evaporated to provide the methyl ester in 98percent yield. 1HNMR (300 MHz, CDCl3) δ 7.57 (d, 1H, J=12 Hz); 7.29 (2H, dd, J=2.5, 0.8 Hz); 7.16 (m, 1H); 3.81 (s, 2H); 3.72 (s, 3H).
98.7%
for 2 h; Reflux
Acetyl chloride (0.08 mL, 1.2 mmol, 0.5 equiv), and 2-(3-bromophenyl)acetic acid (0.5 g, 2.3 mmol, 1.0 equiv) were added to MeOH (10 mL) and the reaction mixture was refluxed for 2 h. After consumption of starting material, the reaction mixture was concentrated and extracted with DCM. The organics were combined and washed with brine and dried over Na2S04, filtered and concentrated in vacuum to give methyl 2-(3-bromophenyl)acetate as colorless oil (0.525 g, 98.7percent). LC-MS (ES) m/z = 229.0, 231.0 [M+H]+ . H NMR (400 MHz, DMSOd6) δ 3.61 (s, 3 H), 3.70 (s, 2 H), 7.26 - 7.30 (m, 2 H), 7.43 - 7.46 (m, 1 H), 7.48 (s, 1 H).
97%
at 10 - 20℃; for 2 h;
a) Synthesis of methyl(3-bromophenyl)acetate25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel and gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise at max. 10° C. with cooling and stirring, and the mixture is subsequently stirred at RT for a further 2 h. The reaction mixture is poured onto ice, rendered alkaline using conc. sodium hydroxide solution and extracted with MTB ether. The combined MTB ether phases are dried and filtered. The solvent is subsequently removed.Yield: 25.44 g=0.111 mol=97percent of methyl(3-bromophenyl)acetate; TLC: CH2Cl2=100; Rf about 0.9; HPLC: RT=2.43 min.
97%
at 10 - 20℃; for 2 h;
a) Synthesis of methyl (3-bromophenyl)acetate 25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel with gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise with cooling and stirring at max. 10° C., and the mixture is subsequently stirred at RT for a further 2 h. The reaction mixture is poured onto ice, rendered alkaline using concentrated sodium hydroxide solution and extracted with MTB ether. The combined MTB ether phases are dried, filtered and stripped off to dryness. Yield: 25.44 g=0.111 mol=97percent of methyl(3-bromophenyl)acetate; TLC: CH2Cl2=100; Rf approx. 0.9 HPLC: RT=2.43 min.
96%
With hydrogenchloride In water at 20 - 58℃; for 2 h;
3-BROMOPHENYLACETIC acid (10000 mg, 46. 50MMOL) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58°C for 2h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35percent ACOET/HEXANES to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96percent). GC- MS (MH+ 230 RT = 9.34 min).
96%
at 0 - 25℃; for 5 h;
Acetyl chloride (0 7ml, 9 3mmol) was added dropwise to a solution of (3-bromo-phenyl)-acetic acid (20 Og, 93mmol) in methanol (500ml) at 0°C The reaction was stirred for 5 hours, allowing the temperature to warm gradually to 25°C The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil in 96percent yield, 20 6g1H NMR (400MHz, CDCI3) δ 3 59 (s, 2H) 3 70 (s, 3H), 7 24-7 17 (m, 2H), 7 37-7 45 (m, 2H), LRMS ESI m/z 253 [M+Na]+
96%
at 20℃;
Intermediate 2. (3-Bromo-phenyl)-acetic acid methyl ester. <n="19"/>[0056] Step A: 3-Bτomophenyl acetic acid (1.17 g, 5.44 mmol) is dissolved inMeOH (15 tnL) containing catalytic amounts of thionyl chloride (0.2 tnL). The solution is stirred at room temperature overnight. The solvent is evaporated, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHCO3- The organic layer is dried (MgSO4), filtered and concentrated to afford the methyl ester 16 (1.20 g, 5.28 mmol, 96percent) as an oil: 1H-NMR (400MHz, CDCl3) δ = 7.44 (s, IH), 7.40 (ddd, J = 2.0, 2.4, 6.8 Hz, IH), 7.20 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H). MS calcd. for C9Hi0BrO2 (M+H"1") 229.1, found 229.0.
95%
Reflux
3-Bromophenylacetic acid (100 g, 0.47 mol) was dissolved in methanol (1000 ml) and concentrated sulfuric acid (1 ml) added and the mixture heated at reflux overnight. The methanol was evaporated and the residue partitioned between dichloromethane (600 ml) and saturated aqueous sodium bicarbonate (200 ml). The organic layer was washed with brine (300 ml), dried over magnesium sulfate and concentrated to give methyl 2-(3-bromophenyl)acetate (102 g, 0.45 mol, 95percent) as an oil. 1H NMR (400 MHz, CDCl3): δ ppm 7.43 (bt, 1H), 7.38 (dt, 1H), 7.15-7.19 (m, 2H), 3.68 (s, 3H), 3.58 (s, 2H)
95%
for 5 h; Dean-Stark; Reflux
2- (3-bromophenyl) acetic acid (1.00 g, 4.65 mmol) was dissolved in freshly distilled methanol (50 ml.) . Added cone. H2S04 (8 drops) and refluxed in a Dean-Stark apparatus for 3 hrs. Reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in CH2C12 (40 mL) and washed with sat. NaHC03 (30 mL x 2) and sat. NaCl (30 mL) . The organic layer was dried (anhydrous sodium sulfate) and concentrated in vacuo. The crude product was chromatographed on silica gel (Hexanes/EtOAc, 5:1) to yield target compound 73. Yield 1.011 g, 95percent. Rf = 0.60, H NMR (400 MHz, Chloroform-d) δ 7.47 - 7.43 (m, 1H) , 7.41 (dt, J = 6.5, 2.2 Hz, 1H) , 7.24 - 7.16 (m, 2H) , 3.70 (s, 3H) , 3.60 (s, 2H) ; [M+H]+ = 230.12 (APCI+) .
94%
at 0 - 80℃; for 3 h;
[0180] To a solution of 2-(3-bromophenyl)acetic acid (5.0 g, 23.3 mmol) in CH3OH (30 mL), was added SOCl2 (3.2 g, 27.0 mmol) at 0 °C. Then the mixture was stirred at 80 °C for 3 hours. The solvent was removed under reduced pressure to give methyl 2-(3- bromophenyl)acetate (5.0 g, yield: 94percent); LC/MS: m/z (M++l) = 231.
91%
at 40℃; for 16 h;
Example 18; Preparation of Methyl (3-Bromophenyl)acetateA stirred solution of (3-bromophenyl)acetic acid (10.0 g, 0.0465 mol) and concentrated sulfuric acid (4.5 mL) in MeOH (230 mL) was heated at 40 0C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was mixed with water (50 mL) and DCM (100 mL). The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10percent EtOAc/hexanes) to give the title compound (19.8 g, 91 percent yield) as a colorless oil.LC-MS (Method 10-90): Rt 3.36 min; mlz 300.4 [M + H]+; 229.6 [M+]. 1H NMR (CD3OD) δ 7.48(s, IH); 7.44(d, IH); 7.26-7.25(m, 2H); 3.71(s, 3H); 3.66(s, 2H).
90%
for 3 h; Reflux
Step 1 : [00152] To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol (150 ml_) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 hours. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1). This gave (3-bromophenyl)acetic acid methyl ester as a colorless oil (11.7 g, 90percent). 1H NMR (400 MHz, CD3OD): δ = 7.46 (m, 1 H), 7.41 (m, 1 H), 7.22 (m, 2H), 3.68 (s, 3H)1 3.65 (s, 2H); LRMS (ESI): m/z = 229 (MH+); HPLC: 3.8 min.
90%
for 3 h; Reflux
[0095] Step 1 : To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol(150 mL) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 h. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1 ). This gave (3- bromophenyl)acetic acid methyl ester as a colorless oil (1 1.7 g, 90percent). 1H NMR (400 MHz, CD3OD): δ = 7.46 (m, 1 H), 7.41 (m, 1 H), 7.22 (m, 2H), 3.68 (s, 3H), 3.65 (s, 2H); LRMS (ESI): m/z = 229 (MH+); HPLC: 3.8 min.
86.1%
Reflux
Methyl 2-(3-bromophenyl) acetateBrTo the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) wasadded SOCI2(2 mL). The reaction solution was stirred and heated to reflux overnight.After the reaction was completed, 200mL of water and 30 mL of NaHCO3 aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2504. After filtration and evaporation of the solvent, the product (11 .Og, 86.1 percent) was obtained.
86.1%
Reflux
To the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) was added SOCI2 (2 mL). The reaction solution was stirred and heated to reflux overnight. After the reaction was completed, 200mL of water and 30 mL of NaHCOs aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the product (1 1 . Og, 86.1 percent) was obtained.
4.9 g
With hydrogenchloride In water for 3 h; Reflux
(3-Bromophenyl)acetic acid 11 (5.0 g, 23.3 mmol) and methanol (50 mL) were refluxed for 3 h in the presence of 0.2 mL of concentrated hydrochloric acid (HCl) to give the methyl (3-bromophenyl)acetate. After neutralization with saturated NaHCO3 and washing with brine, a pure product was obtained from the diethyl ether extract. This methyl acetate (4.9 g, 21.4 mmol) in dry THF (35 mL) was added dropwise to a stirred solution of 2.0 mol/L lithium diisopropylamide (LDA) (12.9 mL, 25.8 mmol) in THF/ethylbenzene/heptane at -78 °C under argon (Ar), and after 30 min, iodomethane (CH3I) (2.0 mL, 32.2 mmol) was added slowly. The resulting solution was stirred for 5 h with the temperature changed from -78 to -40 °C, then evaporated to dryness, and extracted with CH2Cl2 (50 mL). Evaporation of the solvent and purification of the residue by silica gel chromatography (n-hexane/AcOEt, 20:1) yielded the title compound as a colorless liquid (77.2percent). 1H NMR (CDCl3) δ: 1.49 (3H, d, J = 7.1 Hz, α-CH3), 3.67 (3H, s, CO2CH3), 3.68 (1H, q, J = 7.1 Hz, CH), 7.18 (1H, t, J = 7.5 Hz, Ar-H5), 7.23 (1H, dt, J = 7.8, 1.7 Hz, Ar-H6), 7.38 (1H, dt, J = 7.3, 1.8 Hz, Ar-H4), 7.44 (1H, st, J = 1.7 Hz, Ar-H2). FAB-MS (m/z): 243.02 (M++H, calcd for C10H1279BrO2: 243.00).
1.97 g
at 0℃; for 2 h; Reflux
Example 5A: Methyl 2-(3 -bromophenyl)acetate j00225j 3-Bromophenylacetic acid (2.0 g, 9.30 mmol) was dissolved in MeOH (46.5mL) and cooled to 0 °C. SOC12 (3.39 mL, 46.5 mmol) was added carefully dropwise.The reaction was then heated to reflux at for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 100percent EtOAc in hexanes to yield Example 5A (1 .97g, 8.60 mmol). 1H NMR (400 MHz, CHLOROFORM-cl) ö ppm 7.44 (1 H, s), 7.36 - 7.43 (1 H, m), 7.15 -7.24 (2 H, m), 3.70 (3 H, s), 3.60 (2 H, s).
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32
[ 1878-67-7 ]
[ 150529-73-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sulfuric acid In methanol for 3 h; Heating / reflux
Step (v); Methyl 3-bromophenylacetate; [Show Image] To 3-bromophenylacetic acid 10.0g (46.5mmol) were added methanol 150ml and sulfuric acid 5ml and the mixture was refluxed for 3 hours. After neutralization with aqueous ammonia and removal of the solvent by distillation, to the residue was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography (SiO2 200g, eluent: Hexane/EtOAc=6/ 1) to give the object compound 10.65g as a colorless oil. Quantitatively 1H NMR (CDCl3) δ 7.44 (1H, s), 7.41 (1H, m), 7.21 (2H, m), 3.71 (3H, s), 3.60 (2H, s).
99%
With sulfuric acid In methanol; dichloromethane; ethyl acetate
Part A 3-Bromophenyl acetic acid (2.0 g, 9.3 mmol) was dissolved in methanol (20 ml) in a 50 ml flask. Concentrated sulfuric acid (2 drops) was added, and the mixture was refluxed under nitrogen for ten hours then concentrated under reduced pressure. The residue was mixed with dichloromethane (20 ml) and saturated sodium bicarbonate solution (10 ml). The organic material was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was flushed through silica gel with hexane/ethyl acetate (3:1), and concentrated to provide 2.12 g (99percent) of methyl (3-bromophenyl)acetate, which was used without further purification.
With trifluoroborane diethyl ether; sodium hydrogencarbonate In dichloromethane; cyclohexane
Preparation D (3-Bromo-phenyl)-acetic acid tert-butyl ester: To a solution of 3-bromo-phenyl-acetic acid (10 gm, 46.5 mmol) and methylene chloride (47 mL) was added a solution of t-butyl-2,2,2-trichloroacetamidate (20.3 g, 93.0 mmol) and cyclohexane (186 mL) followed by borontrifluoride etherate (0.93 mL, 7.3 mmol). After stirring overnight, solid sodium bicarbonate was added and the reaction then filtered through a pad of silica gel utilizing methylene chloride as solvent. Concentration gave 9.11 g (72percent) of a colorless oil. 1H-NMR (CDCl3, δ): 1.41 (s, 9H), 3.46 (s, 2H), 7.1-7.4 (multiplets, 4H).
BH3-Me2S (7 ml_ of a 2M solution in THF, 14.0 mmol) was added to a cold (0 0C) solution of 3-bromophenylacetic acid (2.00 g, 9.3 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 20 hours and re-cooled to 0 0C. Water (10 ml.) was added dropwise. The organic layer was separated, washed with brine (20 mL), dried (MgSO4), filtered and concentrated under reduced pressure to leave a colourless oil. Purification by column chromatography (50 % EtOAc in heptane) afforded the title compound as a colourless oil (1.47 g, 79 % yield). m/z 224/226 [M+H]+. 1H NMR (300 MHz, CDCI3) 7.41-7.35 (2H, m), 7.23-7.16 (2H, m), 3.87 (2H, t, J=6.5 Hz), 2.86 (2H, t, J=6.5 Hz).
Production Example 8; Synthesis of N-(4-{2-[3-(2-[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-.,3-thiazol-2-yl)acetamide hydrochloride; Step 1; To a suspension of lithium aluminum hydride in drytetrahydrofuran (50 ml) was added (3-bromophenyl)acetic acid(10 g) in tetrahydrofuran (100 ml) under ice cooling. Themixture was refluxed for 2 hurs. After cooling, to thereaction mixture were added water and aqueous Rochelle salt.The mixture was stirred for another 30 min. Aqueous layer wasextracted with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, and concentrated in vacua to give2-(3-bromophenyl)ethanol. This compound was used for the nextreaction without further purification.
With benzophenone; potassium; In tetrahydrofuran; methanol;
A. 2-(3-Bromophenyl)ethan-1-ol To a solution of 10.0 g (46.5 mmol, Aldrich) of 3-bromophenylacetic acid in 100 mL of dry tetrahydrofuran (distilled from potassium/benzophenone), cooled to 0 C., was added dropwise over 40 minutes 61 mL (61 mmol, 1M/tetrahydrofuran, Aldrich) of borane-tetrahydrofuran solution. The reaction was stirred at room temperature for 16 hours, then cooled to 0 C. and quenched by the dropwise addition of 10 mL methanol. The reaction mixture was concentrated in vacuo and azeotroped with two 10-mL portions of methanol to give 9.35 g (46.5 mmol, 100%) of alcohol A as a clear oil.
In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Step 1--Preparation of 2-(3-bromophenyl)ethanol; reduction of 3-bromophenylacetic acid via diborane reduction A 2 liter 4 neck flask stirred under nitrogen, equipped with condenser and addition funnel, was charged with 75 gms of 3-bromophenylacetic acid (0.34 mole), in 100 ml of THF. Then 350 ml of 1M diborane-THF complex (0.35 mole) was added dropwise. Upon addition, gas evolved and the reaction was cooled to maintain the temperature below 10 C. After the addition was complete, the reaction was stirred at room temperature until, by thin layer chromatography, the reaction was complete. The reaction was quenched by adding ice water and the product was extracted into ether then washed with 5% NaOH, 5% HCl, water and dried over magnesium sulfate. After concentration, 77.4 gms of product resulted and was chlorinated directly. NMR (90 MHz): 2.7-2.9(m, 3H), 3.7-3.9(t, 2H) and 7.1-7.4(m, 4H).
3-Bromophenyl acetic acid (10 g, 0.0465 mol), dissolved in THF (50 mJL), was added dropwise added to a LAH (3.5 g, 0.93 mol) suspension in THF (100 mL), at 00C under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature before being quenched with water (9.5 mL), 10% NaOH (9.5 mL) and then water (9.5 mL) again. Precipitated solid was filtered and the residue was washed with DCM. The filtrate was concentrated to afford 8.3 g of the sub-title compound as pale yellow liquid.
With borane-THF; In tetrahydrofuran; at 20℃;
Step 1 [0356] 2-(3-Bromophenyl)ethanol 2-(3-bromophenyl)acetic acid (10.0 g, 0.046 mol) in THF (150 mL), 1 M BH3-THF (100 mL, 100 mmol) was dropwise added at RT. The mixture was stirred overnight, concentrated, diluted with H2O (100 mL), and extracted with EtOAc (100 m×3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to afford the crude product 2-(3-bromophenyl)ethanol (9.0 g, 97%) as a colorless oil, which was directly used for next step without further purification. MS (ES+) C8H9BrO requires: 200, 202. found: 201 [M+H]+, 203 [M+2+H]+(1:1).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 4.5h;Reflux;
General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography.
With diborane; In tetrahydrofuran;
Step 1 To a solution of 3-bromophenylacetic acid (10 g, 46.5 mmol) in tetrahydrofuran (100 ml) at 0 C. was added diborane (70 ml, 1.0 M solution in tetrahydrofuran). The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was cooled to 0C. and water was added dropwise (50 ml). The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40-60% ethyl acetate/hexane) to give 3-(2-hydroxyethyl)bromobenzene (9.0 g).
Stage #1: 3-Bromophenylacetic acid With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 3h;
Stage #2: dimethyl amine In dichloromethane; water at 0 - 20℃; for 2h;
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 0 - 20℃;
To dichloromethane (580 ml) solution of 25 g (116 mmol) of 3-bromophenylacetic acid were added 9.4 ml (232 mmol) of methanol and 0.15 g (1.2 mmol) of 4-(dimethylamino)pyridine. After cooling with ice, 26.8 g (140 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added thereto, and the resulting mixture was stirred overnight with gradually warming up to room temperature. The reaction mixture was washed with hydrochloric acid, saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. After filtrating and concentrating under reduced pressure, 27.3 g (quantitative) of the entitled compound was obtained as a pale yellow oil.1H-NMR(CDCl3)delta: 3.60(2H, s), 3.70(3H, s), 7.16-7.23(2H, m), 7.39-7.45(2H, m).
100%
With sulfuric acid;Heating / reflux;
A mixture of 3-bromophenylacetic acid (5.29 g, 24.6 mmol) and concentrated sulfuric acid (100 muL) in anhydrous methanol (40 mL) was refluxed overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo to give 121A (5.82 g, 100%) as pale yellow oil. LC-MS m/z: 228.18 (M+H)+.
99%
With acetyl chloride; for 2h;Reflux;
INTERMEDIATE 6(3-BromophenyDacetic acid methyl ester Acetyl chloride (0.5 niL) was added to MeOH (100 mL). 3-Bromophenylacetic acid (15 g, 69.8 mmol) was added, and the mixture refluxed for 2 h. The solvent was removed in vacuo and the residue partitioned between DCM and water (50 mL each). The aqueous phase was extracted with DCM (20 mL) and the combined organic phases were dried (MgSO4) and the solvent removed in vacuo to give the title compound (15.85 g, 99%) as a colourless oil. deltaH (CDCl3) 7.44 (s, IH), 7.37-7.43 (m, IH), 7.15-7.24 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H).
98%
With thionyl chloride;Heating / reflux;
To a solution of 3-bromophenylacetic acid (1 g, 4.65 mmol) in 20 mL MeOH at 0 C. was added thionyl chloride (0.51 mL, 1.5 eq.) dropwise. The resulting solution was then refluxed overnight under N2. The reaction was cooled to rt and the solvent was removed in vacuo. The residue was taken up in EtOAc, washed with sat'd. NaHCO3 and brine, then dried over Na2SO4, filtered and evaporated to provide the methyl ester in 98% yield. 1HNMR (300 MHz, CDCl3) delta 7.57 (d, 1H, J=12 Hz); 7.29 (2H, dd, J=2.5, 0.8 Hz); 7.16 (m, 1H); 3.81 (s, 2H); 3.72 (s, 3H).
98.7%
With acetyl chloride; for 2h;Reflux;
Acetyl chloride (0.08 mL, 1.2 mmol, 0.5 equiv), and 2-(3-bromophenyl)acetic acid (0.5 g, 2.3 mmol, 1.0 equiv) were added to MeOH (10 mL) and the reaction mixture was refluxed for 2 h. After consumption of starting material, the reaction mixture was concentrated and extracted with DCM. The organics were combined and washed with brine and dried over Na2S04, filtered and concentrated in vacuum to give methyl 2-(3-bromophenyl)acetate as colorless oil (0.525 g, 98.7%). LC-MS (ES) m/z = 229.0, 231.0 [M+H]+ . H NMR (400 MHz, DMSOd6) delta 3.61 (s, 3 H), 3.70 (s, 2 H), 7.26 - 7.30 (m, 2 H), 7.43 - 7.46 (m, 1 H), 7.48 (s, 1 H).
97%
With thionyl chloride; at 10 - 20℃; for 2h;
a) Synthesis of methyl(3-bromophenyl)acetate25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel and gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise at max. 10 C. with cooling and stirring, and the mixture is subsequently stirred at RT for a further 2 h. The reaction mixture is poured onto ice, rendered alkaline using conc. sodium hydroxide solution and extracted with MTB ether. The combined MTB ether phases are dried and filtered. The solvent is subsequently removed.Yield: 25.44 g=0.111 mol=97% of methyl(3-bromophenyl)acetate; TLC: CH2Cl2=100; Rf about 0.9; HPLC: RT=2.43 min.
97%
With thionyl chloride; at 10 - 20℃; for 2h;
a) Synthesis of methyl (3-bromophenyl)acetate 25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel with gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise with cooling and stirring at max. 10 C., and the mixture is subsequently stirred at RT for a further 2 h. The reaction mixture is poured onto ice, rendered alkaline using concentrated sodium hydroxide solution and extracted with MTB ether. The combined MTB ether phases are dried, filtered and stripped off to dryness. Yield: 25.44 g=0.111 mol=97% of methyl(3-bromophenyl)acetate; TLC: CH2Cl2=100; Rf approx. 0.9 HPLC: RT=2.43 min.
96%
With hydrogenchloride; In water; at 20 - 58℃; for 2h;
3-BROMOPHENYLACETIC acid (10000 mg, 46. 50MMOL) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58C for 2h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35% ACOET/HEXANES to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96%). GC- MS (MH+ 230 RT = 9.34 min).
96%
With acetyl chloride; at 0 - 25℃; for 5h;
Acetyl chloride (0 7ml, 9 3mmol) was added dropwise to a solution of (3-bromo-phenyl)-acetic acid (20 Og, 93mmol) in methanol (500ml) at 0C The reaction was stirred for 5 hours, allowing the temperature to warm gradually to 25C The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil in 96% yield, 20 6g1H NMR (400MHz, CDCI3) delta 3 59 (s, 2H) 3 70 (s, 3H), 7 24-7 17 (m, 2H), 7 37-7 45 (m, 2H), LRMS ESI m/z 253 [M+Na]+
96%
thionyl chloride; at 20℃;
Intermediate 2. (3-Bromo-phenyl)-acetic acid methyl ester. <n="19"/>[0056] Step A: 3-Btauomophenyl acetic acid (1.17 g, 5.44 mmol) is dissolved inMeOH (15 tnL) containing catalytic amounts of thionyl chloride (0.2 tnL). The solution is stirred at room temperature overnight. The solvent is evaporated, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHCO3- The organic layer is dried (MgSO4), filtered and concentrated to afford the methyl ester 16 (1.20 g, 5.28 mmol, 96%) as an oil: 1H-NMR (400MHz, CDCl3) delta = 7.44 (s, IH), 7.40 (ddd, J = 2.0, 2.4, 6.8 Hz, IH), 7.20 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H). MS calcd. for C9Hi0BrO2 (M+H"1") 229.1, found 229.0.
95%
With sulfuric acid;Reflux;
3-Bromophenylacetic acid (100 g, 0.47 mol) was dissolved in methanol (1000 ml) and concentrated sulfuric acid (1 ml) added and the mixture heated at reflux overnight. The methanol was evaporated and the residue partitioned between dichloromethane (600 ml) and saturated aqueous sodium bicarbonate (200 ml). The organic layer was washed with brine (300 ml), dried over magnesium sulfate and concentrated to give methyl 2-(3-bromophenyl)acetate (102 g, 0.45 mol, 95%) as an oil. 1H NMR (400 MHz, CDCl3): delta ppm 7.43 (bt, 1H), 7.38 (dt, 1H), 7.15-7.19 (m, 2H), 3.68 (s, 3H), 3.58 (s, 2H)
95%
With sulfuric acid; for 5h;Dean-Stark; Reflux;
2- (3-bromophenyl) acetic acid (1.00 g, 4.65 mmol) was dissolved in freshly distilled methanol (50 ml.) . Added cone. H2S04 (8 drops) and refluxed in a Dean-Stark apparatus for 3 hrs. Reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in CH2C12 (40 mL) and washed with sat. NaHC03 (30 mL x 2) and sat. NaCl (30 mL) . The organic layer was dried (anhydrous sodium sulfate) and concentrated in vacuo. The crude product was chromatographed on silica gel (Hexanes/EtOAc, 5:1) to yield target compound 73. Yield 1.011 g, 95%. Rf = 0.60, H NMR (400 MHz, Chloroform-d) delta 7.47 - 7.43 (m, 1H) , 7.41 (dt, J = 6.5, 2.2 Hz, 1H) , 7.24 - 7.16 (m, 2H) , 3.70 (s, 3H) , 3.60 (s, 2H) ; [M+H]+ = 230.12 (APCI+) .
94%
With thionyl chloride; at 0 - 80℃; for 3h;
[0180] To a solution of 2-(3-bromophenyl)acetic acid (5.0 g, 23.3 mmol) in CH3OH (30 mL), was added SOCl2 (3.2 g, 27.0 mmol) at 0 C. Then the mixture was stirred at 80 C for 3 hours. The solvent was removed under reduced pressure to give methyl 2-(3- bromophenyl)acetate (5.0 g, yield: 94%); LC/MS: m/z (M++l) = 231.
91%
With sulfuric acid; at 40℃; for 16h;
Example 18; Preparation of Methyl (3-Bromophenyl)acetateA stirred solution of (3-bromophenyl)acetic acid (10.0 g, 0.0465 mol) and concentrated sulfuric acid (4.5 mL) in MeOH (230 mL) was heated at 40 0C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was mixed with water (50 mL) and DCM (100 mL). The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexanes) to give the title compound (19.8 g, 91 % yield) as a colorless oil.LC-MS (Method 10-90): Rt 3.36 min; mlz 300.4 [M + H]+; 229.6 [M+]. 1H NMR (CD3OD) delta 7.48(s, IH); 7.44(d, IH); 7.26-7.25(m, 2H); 3.71(s, 3H); 3.66(s, 2H).
90%
toluene-4-sulfonic acid; for 3h;Reflux;
Step 1 : [00152] To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol (150 ml_) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 hours. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1). This gave (3-bromophenyl)acetic acid methyl ester as a colorless oil (11.7 g, 90%). 1H NMR (400 MHz, CD3OD): delta = 7.46 (m, 1 H), 7.41 (m, 1 H), 7.22 (m, 2H), 3.68 (s, 3H)1 3.65 (s, 2H); LRMS (ESI): m/z = 229 (MH+); HPLC: 3.8 min.
90%
With toluene-4-sulfonic acid; for 3h;Reflux;
[0095] Step 1 : To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol(150 mL) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 h. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1 ). This gave (3- bromophenyl)acetic acid methyl ester as a colorless oil (1 1.7 g, 90%). 1H NMR (400 MHz, CD3OD): delta = 7.46 (m, 1 H), 7.41 (m, 1 H), 7.22 (m, 2H), 3.68 (s, 3H), 3.65 (s, 2H); LRMS (ESI): m/z = 229 (MH+); HPLC: 3.8 min.
86.1%
With thionyl chloride;Reflux;
Methyl 2-(3-bromophenyl) acetateBrTo the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) wasadded SOCI2(2 mL). The reaction solution was stirred and heated to reflux overnight.After the reaction was completed, 200mL of water and 30 mL of NaHCO3 aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2504. After filtration and evaporation of the solvent, the product (11 .Og, 86.1 %) was obtained.
86.1%
With thionyl chloride;Reflux;
To the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) was added SOCI2 (2 mL). The reaction solution was stirred and heated to reflux overnight. After the reaction was completed, 200mL of water and 30 mL of NaHCOs aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the product (1 1 . Og, 86.1 %) was obtained.
acetyl chloride; at 0 - 20℃; for 5h;
Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromophenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a colourless oil, 20.6g.1H nmr (CDCl3, 400MHz) delta: 3.59 (s, 2H), 3.70 (s, 3H), 7.17-7.24 (m, 2H), 7.37-7.45 (m, 2H) LRMS :m/z ES+ 253 [M+Na]+.
With acetyl chloride; at 0 - 20℃; for 5h;
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly-added to a solution of (3-bromo- phenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400MHz, CDCI3) : 8 : 3.59 (2H, s), 3.70 (3H, s), 7.17-7. 24 (2H, m), 7.37-7. 45 (2H, m); LRMS ESI m/z 253 [M+Na] +
With acetyl chloride; at 0 - 20℃; for 5h;
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 C. under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400 MHz, CDCl3): delta=7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+253.
With acetyl chloride; at 0 - 20℃; for 5h;
Preparation 28: Methyl (3-bromophenyl)acetate Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromophenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6g). 1H NMR (400MHz, CDCl3): delta = 7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 253.
With acetyl chloride; at 0 - 20℃; for 5h;
Preparation 3 (3-Bromo-phenyl)-acetic acid methyl ester Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromophenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0C under nitrogen and the reaction was allowed to warm gradually to room temperature over 5 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane, dried (sodium sulphate) and concentrated under reduced pressure to give the title compound as a colourless oil, 20.6g. 1H NMR (CDCl3, 400MHz) delta: 3.59(s, 2H), 3.70(s, 3H), 7.17-7.24(m, 2H), 7.37-7.45(m, 2H) LRMS:m/z ES+ 253 [M+Na]+
With acetyl chloride; at 0 - 20℃; for 5h;
Acetyl chloride (0.7 ml, 9.3 mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at 0 C. under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400 MHz, CDCl3): delta=7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+253.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 16h;
A solution of 3-bromophenylacetic acid (2.0 g, 9.3 mmol) and 4-dimethylamino pyridine (1.1 g, 9.3 mmol) in methanol (20 mL) was treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC) (2.1 g, 11 mmol). Reaction stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water, saturated sodium bicarbonate, 1N phosphoric acid, and brine before drying over Na2SO4, filtering, and concentrating under reduced pressure to provide the title compound.
With thionyl chloride; at 20℃;
[0030] Step A: 3-Bromophenyl acetic acid 34 (1.17 g, 5.44 mmol) is dissolved inMeOH (15 mL) containing catalytic amounts of thionyl chloride (0.2 mL). The solution is stirred at rt overnight. The solvent is evaporated, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHCCb. The organic layer is dried (MgSO4), filtered and concentrated to afford the methyl ester 35 as an oil: 1H-NMR (400MHz, CDCl3) delta = 7.44 (s, IH), 7.40 (ddd, J = 2.0, 2.4, 6.8 Hz, IH), 7.20 (m, 2H), 3.70 (ss 3H), 3.59 (s, 2H). MS calcd. for C9Hi0BrO2 (M+H4) 229.1, found 229.0.
With thionyl chloride; at 65℃; for 5h;
Step 1: (3-Bromo-phenyl)-acetic acid methyl ester To 3-bromophenylacetic acid (5.03 g, 23.4 mmol) in MeOH (50 mL) was added thionyl chloride (3.4 mL, 46.8 mmol), and the reaction was stirred at 65 C. for 5 hours. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The mixture was basified with 1N aqueous NaOH, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound.
With acetyl chloride; at 0 - 20℃; for 5h;
Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacua and the residue dissolvedin dichloromethane, dried (sodium sulfate) and concentrated in vacua to givethe title compound as a colourless oil (20.6g).
With acetyl chloride; at 0 - 20℃; for 5h;
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly added to a solution of (3- bromophenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400MHz, CDCI3) : 6 : 3.59 (2H, s), 3.70 (3H, s), 7.17-7. 24 (2H, m), 7.37-7. 45 (2H, m). LRMS ESI m/z 253 [M+Na] +.
4.9 g
With hydrogenchloride; In water; for 3h;Reflux;
(3-Bromophenyl)acetic acid 11 (5.0 g, 23.3 mmol) and methanol (50 mL) were refluxed for 3 h in the presence of 0.2 mL of concentrated hydrochloric acid (HCl) to give the methyl (3-bromophenyl)acetate. After neutralization with saturated NaHCO3 and washing with brine, a pure product was obtained from the diethyl ether extract. This methyl acetate (4.9 g, 21.4 mmol) in dry THF (35 mL) was added dropwise to a stirred solution of 2.0 mol/L lithium diisopropylamide (LDA) (12.9 mL, 25.8 mmol) in THF/ethylbenzene/heptane at -78 C under argon (Ar), and after 30 min, iodomethane (CH3I) (2.0 mL, 32.2 mmol) was added slowly. The resulting solution was stirred for 5 h with the temperature changed from -78 to -40 C, then evaporated to dryness, and extracted with CH2Cl2 (50 mL). Evaporation of the solvent and purification of the residue by silica gel chromatography (n-hexane/AcOEt, 20:1) yielded the title compound as a colorless liquid (77.2%). 1H NMR (CDCl3) delta: 1.49 (3H, d, J = 7.1 Hz, alpha-CH3), 3.67 (3H, s, CO2CH3), 3.68 (1H, q, J = 7.1 Hz, CH), 7.18 (1H, t, J = 7.5 Hz, Ar-H5), 7.23 (1H, dt, J = 7.8, 1.7 Hz, Ar-H6), 7.38 (1H, dt, J = 7.3, 1.8 Hz, Ar-H4), 7.44 (1H, st, J = 1.7 Hz, Ar-H2). FAB-MS (m/z): 243.02 (M++H, calcd for C10H1279BrO2: 243.00).
1.97 g
With thionyl chloride; at 0℃; for 2h;Reflux;
Example 5A: Methyl 2-(3 -bromophenyl)acetate j00225j 3-Bromophenylacetic acid (2.0 g, 9.30 mmol) was dissolved in MeOH (46.5mL) and cooled to 0 C. SOC12 (3.39 mL, 46.5 mmol) was added carefully dropwise.The reaction was then heated to reflux at for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 100% EtOAc in hexanes to yield Example 5A (1 .97g, 8.60 mmol). 1H NMR (400 MHz, CHLOROFORM-cl) oe ppm 7.44 (1 H, s), 7.36 - 7.43 (1 H, m), 7.15 -7.24 (2 H, m), 3.70 (3 H, s), 3.60 (2 H, s).
With sulfuric acid; at 20℃; for 18h;
[3-BROMOPHENYLACETIC] acid (14. [38G,] 66.90mmol) is dissolved in methanol (100 ml). Concentrated sulfuric acid (2 [ML)] is added dropwise and the reaction mixture is stirred at room temperature for 18 hours. 80% of the solvent is removed in vacuo and the reaction mixture is partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer is washed with water (150 ml) and brine (150 ml), dried over [MGSO4,] filtered and the solvent removed in vacuo to give the title compound. [1H] nmr [(CDCIA,] 400 MHz); 7.20 (m, 2H), 6.95 (m, 2H), 3.50 (s, 3H), 3.35 (s, 2H)
With acetyl chloride; for 24h;
a) (3-Bromo-phenyl)-acetic acid methyl ester; Acetyl chloride (5mL) was added to a solution of (3-bromo-phenyl)-acetic acid (1Og) in I0 methanol (25OmL). Evaporation after 24 hours afforded the subtitle product, as an oil (10.9g).1H NMR (300 MHz, CDCl3) delta 7.46 - 7.37 (m, 2H), 7.23 - 7.16 (m, 2H), 3.70 (s, 3H), 3.60 (s, 2H).
With thionyl chloride; at 65℃; for 5h;
Step 1: (3-Bromo-phenyI)-acetic acid methyl ester[00501] To 3-bromophenylacetic acid (5.027g, 23.4mmol) in MeOH (5OmL) was added thionyl chloride (3.4mL, 46.8mmol), and the reaction was stirred at 650C for 5 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated and the residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. IN Aqueous NaOH was added to adjust the pH to basic, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO^ filtered, and concentrated to give the title compound.
sulfuric acid;Heating / reflux;
Example Il:; (5-{4-[2-(2,4-Dichloro-phenoxy)-ethyl-carbamoyl]-5-phenyl- isoxazol-3-yl} -phenyl)-acetic acid. [00159] Step A: 3-Bromophenyl acetic acid 45 (1.17 g, 5.44 mmol) is dissolved in MeOH (15 mL) containing catalytic amounts of cone. H2S04 (0.2 mL). The solution is heated to reflux overnight. The solvent is evaporated, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHC03. The organic layer is dried (MgS04), filtered and concentrated to afford the methyl ester 46 as an oil: ¹H-NMR (400MHz, CDC13) No. = 7.44 (s, 1H), 7.40 (ddd, J = 2.0, 2.4, 6.8 Hz, 1H), 7.20 (m, 2H), 3.70 (s, 3H), 3.59 (s, 2H). MS calculated for C9HioBr02 (M+H+) 229.1, found 229.0.
With hydrogenchloride; at 0 - 20℃;
Hydrogen chloride is bubbled through MeOH (80 mL) and the solution is stirred at O0C for 10 minutes. (3-bromo-phenyl)-acetic acid (30 g, 139.5 mmol) is added in portions and the reaction is stirred overnight, while warming to room temperature. The solution is concentrated in vacuo and the residue is dissolved in EtOAc (200 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3-bromo-phenyl)-acetic acid methyl ester (32 g) used in the next step without further purification. MS: 230 (M+H); 1H NMR (300 MHz, CDCl3): delta 7.45 (2H, m), 7.25 (2H, m), 3.72 (3H, s), 3.6 (2H, s).
Preparation of ethyl 3-bromophenylacetate: 2.5 ml of conc. sulphuric acid were added to a solution of 25 g (116 mmol) of 3-bromophenylacetic acid in 170 ml of ethanol. The mixture was heated under reflux for 20 h. After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in 800 ml of ethyl acetate. The organic phase was washed three times with in each case 50 ml of saturated aqueous sodium bicarbonate solution and twice with in each case 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and, after filtration, concentrated under reduced pressure. The residue obtained in this manner was purified by column chromatography on silica gel using the mobile phase hexane/0-20% ethyl acetate. This gave 27.8 g (98% of theory) of ethyl 3-bromophenylacetate. Preparation of the Title Compound:
97%
With thionyl chloride; at 0℃; for 2h;Reflux;
Into a 250-mL round-bottom flask, were placed 2-(3-bromophenyl)acetic acid (5 g, 23.25mmol, 1 .00 equiv), ethanol (80m l_). This was followed by the addition of thionyl chloride (5.6 g, 46.28mmol, 2.00 equiv) dropwise with stirring at 0C. The resulting solution was heated to reflux for 2 h. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated. This resulted in 5.5 g (97%) of ethyl 2-(3-bromophenyl)acetate as colorless oil.
95%
sulfuric acid; at 80℃;
Compound I: Synthesis using modified procedure of Sonogashira: Step i: To a solution/suspension of 3-bromophenylacetic acid (5.02g, 23.33 mmol) in ethanol (100 ml.) at room temperature was added concentrated sulfuric acid (1mL). The colorless solid was then stirred overnight at 8O0C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with 2 x ethyl acetate (25 mL) and brine (20 mL). The combinated organic layers were washed with 2 x saturated solution of NaHCO3 (25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95%). 1H-NMR (400 MHz, CDCI3): delta 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H)1 7.44 (d, J = 1.56 Hz, 1 H).
95%
With sulfuric acid; at 80℃;
Example 1: Detailed experimental procedures for the preparation of the sodium salt of 3-pentylphenylacetic acid (hereinafter Compound I)Instrumentation:[00108] All HPLC chromatograms and mass spectra were recorded on an HP 1100 LC-MS Agilent instrument using an analytical C18 column (250 x 4.6 mm, 5 microns) with a gradient over 5 min of 15-99% CH3CN-H2O with 0.01% TFA as the eluant and a flow of 2 mL/min.Compound I: Synthesis using modified procedure of Sonogashira:Step i:[00109] To a solution/suspension of 3-bromophenylacetic acid (5.02g, 23.33 mmol) in ethanol (100 ml_) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solid was then stirred overnight at 8O0C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 ml_), water (25 mL) and the two layers were separated. The aqueous layer was extracted with 2 x ethyl acetate (25 mL) and brine (20 mL). The combinated organic layers were washed with 2 x saturated solution of NaHCO3 (25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95%). 1H-NMR (400 MHz, CDCI3): delta 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H), 7.44 (d, J = 1.56 Hz, 1H).
95%
With sulfuric acid; at 20 - 80℃;
[0088] Step 1 : To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol (100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solution was then stirred overnight at 80C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2 chi 25 mL) and brine (20 mL). The combinated organic layers were washed with saturated solution of NaHC03 (2 chi 25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95%). 1H-NMR (400 MHz, CDCI3): delta 1.26 (t J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1 H), 7.44 (d, J = 1.56 Hz, 1 H).
95%
With sulfuric acid; at 80℃;
[00100] To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol(100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solidwas then stirred overnight at 80C. The solution was concentrated under reduced pressure. Theresidue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated.The aqueous layer was extracted with ethyl acetate (2 x 25 mL) and brine (20 mL). Thecombinated organic layers were washed with saturated solution of NaHCO3 (2 x 25 mL), brine(25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness.This gave a light yellow oil (5.4 g, 95%). 1H-NMR (400 MHz, CDCI3): oe 1.26 (t, J = 4.7 Hz, 3H),3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1H), 7.44 (d, J =1.56 Hz, IH).
95%
With sulfuric acid; at 80℃;
To a solution/suspension of 3-bromophenylacetic acid (5.02 g, 23.33 mmol) in ethanol (100 mL) at room temperature was added concentrated sulfuric acid (1 mL). The colorless solid was then stirred overnight at 80C. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), water (25 mL) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2 chi 25 mL) and brine (20 mL). The combinated organic layers were washed with saturated solution of NaHC03 (2 x 25 mL), brine (25 mL) and dried over sodium sulfate. After filtration the solution it was evaporated to dryness. This gave a light yellow oil (5.4 g, 95%). 1H-NMR (400 MHz, CDCIa): delta 1.26 (t, J = 4.7 Hz, 3H), 3.57 (s, 2H), 4.15 (Q, J = 7.0 and 14.3 Hz, 2H), 7.17-7.26 (m, 2H), 7.38-7.44 (m, 1 H), 7.44 (d, J = 1.56 Hz, 1 H).
93.4%
With hydrogenchloride; at 0 - 20℃; for 5.08333h;
74 lStep 1. HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at O0C for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford (3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4%] as an oil, which is used without further purification.
93%
With sulfuric acid;Reflux;
3-Bromophenylacetic acid, 35i-a, (50g, 0.23mol) was dissolved in ethanol (250 mL) and sulfuric acid was added drop-wise. The mixture was heated to reflux and stirred overnight. The solution was adjusted to about a pH of 7-8 with sodium hydroxide solution and concentrated in vacuo. The water phase was extracted with ethyl atetate (3 x 150 mL) and the combined organics was washed with brine (50 mL) and dried, concentrated to give the compound, 35i-b, (52.6g, 93%) as colorless oil. 1H NMR (300 MHz, CDCI3) delta 1.24-1.29 (m, 3H), 3.58 (s, 2H), 4.11-4.19 (m, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 2H). LC-MS (M+H)+243, 245
93.4%
With hydrogenchloride; at 0 - 20℃; for 5.08333h;
HCl is bubbled through a solution of 3-bromophenyl acetic acid (10.5 g, 46.5 mmol) in EtOH (70 mL) chilled at O0C for 5 minutes. The flask is capped and stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is taken up with water (80 mL) and extracted twice with EtOAc (70 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford f3-bromo-phenyl)-acetic acid ethyl ester [10.55 g, 93.4%] as an oil, which is used without further purification.
88%
With thionyl chloride; at 0 - 85℃;
Example A6; N-[(1-[3-[8-methyl-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl]phenyl]-1-methylethyl]amine; A6.1 tert-butyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamate; A6.1a: Ethyl 2-(3-bromophenyl)acetate; Commercially available 2-(3-bromophenyl)acetic acid (13 g 0.06 mol) was dissolved in ethanol (130 ml) and cooled to 0 C. Thionyl chloride (20 ml) was added drop wise. The mixture was heated to 85 C. over night. Reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% NaHCO3, water, dried over anhydrous sodium sulfate and concentrated to give 13 g (88%) of A6.1a.
88%
With thionyl chloride; at 20 - 80℃; for 15h;Product distribution / selectivity;
To an ice cooled solution of 2-(3-bromophenyl)acetic acid (1 g, 4.6 mmol) in EtOH (10 mL), thionyl chloride (0.67 mL, 9.3 mmol) was added dropwise. The reaction mixture was then warmed to room temperature heated at 80 C. for 15 h. The reaction was monitored by TLC and after completion of the reaction, the reaction mixture was concentrated under vacuo and water was added to the residue. A saturated aqueous solution of NaHCO3 was added to the solution until the pH of the solution was 9. Then, the aqueous solution was extracted with EtOAc, the organic layer was dried over Na2SO4, concentrated under vacuum, and purified by column chromatography (silica gel) to yield ethyl 2-(3-bromophenyl)acetate yield 1.13 g. (88%).
With sulfuric acid; at 20℃;
3-Bromophenylacetic acid (5.03 g) was dissolved in ethanol (40 ml), conc. sulfuric acid (0.5 ml) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate and brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (5.4 g).
With hydrogenchloride; at 20℃; for 16h;
Preparation 22; 1-Bbetanzyl-3-(3-bromo-phenyl)-pyiotatauolidl?e-3-carboxyllc acid ethyl ester; Step i:; A solution of 2-bromophenyl acetic acid (25.0 g, 116 mmol) in EtOH (200 mL) was saturated with HCI gas. After the mixture had cooled to rt, it was re-saturated with HCI and stirred for 16h. The reaction was concentrated, dissolved in EtOAc and washed with sat.aq. NaHCO3 and brine, dried (Na2SO4) and concentrated to yield 33.18g of 3-bromo-phenyl}- acetic acid ethyl ester as a yellow oil: NMR (CDCI3) delta 7.42 (d, J = 1.3 Hz, 1H), 7.39-7.36 (m, 1h), 7.21-7.14 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.55 (s, 2H), 1.23 (t, J = 7.3 Hz, 3H).
With sulfuric acid; for 2h;Heating / reflux;
Preparation 2.6; Ethyl 2-(3-bromophenyl)-3-hydroxy-2-propenoate (III); A) Ethyl 3-bromophenylacetate; 5 g of 3-bromophenylacetic acid are dissolved in 80 ml of ethanol, 3 ml of concentrated H2SO4 are added and then the mixture is heated at reflux for two hours. The ethanol is evaporated, neutralization is carried out with a saturated K2CO3 solution and then extraction is carried out with AcOEt. The organic phase is dried over MgSO4. 5.2 g of the expected compound are obtained in the liquid form. NMR CDCl3 (300 MHz): 1.18 ppm:t:3H; 3.50 ppm:s:2H; 4.08 ppm:q:2H; 7.09-7.37 ppm:unresolved peak:4H.
With sulfuric acid; for 2h;Reflux;
Example 23Synthesis of (4'-{-4-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-3-yl)-acetic acid (Compound 12)3-Bromophenylacetic acid (0.31 mmol) was treated with concentrated sulfuric acid in ethanol at reflux for 2 hours to give (3-bromo-phenyl)-acetic acid ethyl ester.Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, (3-bromo-phenyl)-acetic acid ethyl ester, and (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) were reacted to provide (4'-{4-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-3-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
With sulfuric acid; for 2h;Heating / reflux;
5 g of 3-bromophenylacetic acid are dissolved in 80 ml of ethanol, 3 ml of concentrated H2SO4 are added and then the solution is heated at reflux for 2 hours. The ethanol is evaporated and the residue is neutralized with saturated K2CO3 solution and then extracted with AcOEt and dried over MgSO4. This gives 5.2 g of the expected compound in liquid form. NMR CDCl3 (300 MHz): 1.18 ppm: t: 3H; 3.50 ppm: s: 2H; 4.08 ppm: q: 2H; 7.09-7.37 ppm: m: 4H.
11.1 g
With sulfuric acid; for 3h;Reflux;
To a solution of 2-(3-bromophenyl)acetic acid 1103 (10.0 g, 46.5 mmol) in 100 mL EtOH was added cone. H2S04 (10 drops) and the mixture heated to relux temperature for 3 hours. The mixture was allowed to cool to room temperature and the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with water (2 x 50 mL), saturated NaHC03 (1 x 25 mL), brine (2 x 25 mL) and dried over Na2S04. The Na2S04 was removed by filtration and the volatiles removed under reduced pressure to give ethyl 2-(3-bromophenyl)acetate 1097 (11.1 grams) as a liquid). 1H NMR 300 MHz CDC13: delta 7.41 (m, 2 H), 7.20 (m, 2H), 4.14 (q, 2H, J= 9.5 Hz), 3.57 (s, 2H), 1.25 (t, 3H, J= 9.5 Hz).
With phosphorus pentoxide; In 1,2-dichloro-benzene; at 20 - 90℃;
(ii) 2- (3-Bromo-phenyl)-1- (5-phenyl-furan-2-yl)-ethanone; 2-Phenyl-furan (119) (50 mg, 0.28 mmol) and (3-bromo-phenyl)- acetic acid (134 mg, 0.63 mmol) were dissolved in ortho- dichlorobenzene (4 ml). P205 (202 mg, 1.42 mmol) was added as a suspension in ortho-dichlorobenzene (2 ml). The reaction mixture was heated to 80C for 2 h and cooled to room temperature overnight. After the addition of further P205 (202 mg, 1.42 mmol), heating was resumed at 90C for 3 h. The reaction mixture was cooled to 0C and quenched with H20 (15 ml). The organic layer was separated and the aqueous layer was washed with DCM (3 x 10 ml). The combined organic layers were dried (MgSO4), filtered and the DCM removed in vacuo. The ortho-dichlorobenzene solution was loaded to a silica-gel column and flushed with heptane (100 ml). The title compound was then eluted with 10% EtOAc in heptane. Yield: 60 mg, 63%; LC/MS tr 1.72 min; MS (ES+) m/z 341,343 (M+H)
38%
With phosphorus pentoxide; In 1,2-dichloro-benzene; at 80℃; for 2h;
Phosphorous pentoxide (2.02 g, 14.20 mmol) suspended in 1,2-dichlorobenzene (60 mL) was added to a mixture of <strong>[17113-33-6]2-phenyl-furan</strong> (23) (500 mg, 2.84 mmol) and 3-bromophenylacetic acid (24) (1.34 g, 6.25 mmol). The reaction mixture was heated to 80 C. for 2 hours and then cooled to ambient temperature. DCM was added, the organic layer washed with water and partially reduced in vacuo. The crude product was purified by Flash Master Jones Chromatography using a 50 g silica cartridge and first eluting with heptane to remove excess 1,2-dichlorobenzene, then 5-10% EtOAc in heptane to give the title compound. Yield: 278 mg, 38%; LC-MS G1.73 min; HPLC Purity: 100%; MS (ES+) m/z 341, 343 (M+H)
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane at 100℃; for 16h; Inert atmosphere;
5.1.14. 3-Biphenylacetic acid (36)
To a stirred solution of (3-bromo)phenylacetic acid (4.00 g, 18.26 mmol), Na2CO3 (2.13 g, 20.1 mmol) and phenylborinic acid (2.45 g, 20.1 mmol) in DME (45 mL) was added tetrakis-triphenylphosphine palladium (200 mg) at room temperature under argon atmosphere. After being stirred at 100 °C for 16 h, the reaction mixture was cooled to room temperature and filtered through Celite to remove the precipitates. The filtrate was diluted with EtOAc, washed with 2 N hydrochloric acid, brine, dried over MgSO4 and evaporated to afford 36 as a pale yellow powder (3.82 g, 99%). 1H NMR (300 MHz, CDCl3): δ 3.72 (s, 2H), 7.25-7.62 (m, 9H).
87%
Stage #1: 3-Bromophenylacetic acid; phenylboronic acid With sodium carbonate In water; isopropyl alcohol at 65℃; for 5h;
Stage #2: With sulfuric acid; water In isopropyl alcohol
1
Synthesis of Compound 4, KX1-307; The synthesis is outlined in Scheme 2. In one synthesis, the reaction commenced with amide bond formation to give 2, followed by a Suzuki coupling with phenylboronic acid to give the meta-biphenyl product Compound 4, KX1-307. In the Suzuki reaction, the biphenyl product was formed but the reaction did not go to completion (by NMR and LCMS) despite additional, time, heat, and extra catalyst. Using silica gel chromatography, the product could not be separated from the bromo starting material 2. Reversing the Suzuki and amide coupling solved the separation problem and successfully produced the metabiphenyl amide KX1-307 as well as 2'-Fluorobiphenyl-4-acetamide KX1-309 (compound 6, Scheme 3). 3-Bromophenylacetic acid (250 mg, 1.163 mmol) and 156 mg (1.1 eq) of phenylboronic acid were dissolved in 6 mL water:isopropanol (6:1). Sodium carbonate (160 mg, 1.3 eq ) was dissolved in 0.5 mL distilled water and added to the reaction followed by Pd(OH)2/C (74 mg, 3 mol %). This was rotated in a 65° C. water bath for 5 hours. The reaction was filtered through filter paper. Filter paper was washed with 25 mL isopropanol:water:1 N NaOH (35:5:1). Washes were combined and acidified to pH 2 with 1 N sulfuric acid. Isopropanol was removed in vacuo and water (10 mL) was added. This aqueous layer was washed with dichloromethane (3×20 mL). Organic washes were combined, dried with sodium sulfate, and removed in vacuo to give 215 mg (87% yield) of the biphenyl product 3. TLC Rf=0.7(long streak, 1:1 EtOAc:DCM). 1HNMR (300 MHz, CDCl3) δ (ppm) 3.72 (s, 2H), 7.26-7.60 (m, 9H). 3-Biphenylacetic acid (3) (100 mg, 0.472 mmol), 3-Fluorobenzylamine (1.1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDCI, (1.1 eq), and HOBT (1-hydroxyenzotriazole, 1.0 eq) were all dissolved in 10 mL anhydrous DCM. After 10 min DIEA (1.1 eq) was added and the reaction was allowed to go overnight. The reaction was diluted to 25 mL and washed with 1N HCl (3×10 L), saturated sodium bicarbonate (3×10 mL), and brine (2×20 mL). The reaction was dried with sodium sulfate and removed in vacuo to give 124 mg pure KX1-307 (83% yield). TLC Rf=0.7(single spot, 1:1 EtOAc:DCM). 1HNMR (300 MHz, CDCl3) δ (ppm) 3.69 (s, 2H) 4.40 (d, 6.0 Hz) 5.77 (s, 1H) 6.86-6.96 (m, 3H) 7.10-7.26 (m, 2H) 7.32 (m, 8H).
(3-Bromo-phenyl)-acetic acid ethyl ester. To a solution of 3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH3CN (150 mL) was added K2CO3 (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol). The mixture was heated at reflux for 2.5 h and was cooled to room temperature. The volatiles were removed in vacuo and water was added. The aqueous solution was extracted with EtOAc (3*) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide (3-bromo-phenyl)-acetic acid ethyl ester (9.30 g) as an oil. 1H NMR (400 MHz, CDCl3) delta 7.43 (s, 1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H), 1.24 (t, 3H).
With potassium carbonate; In water; acetonitrile;
(3-Bromo-phenyl)-acetic acid ethyl ester To a solution of 3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH3CN (150 mL) was added K2CO3 (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol). The mixture was heated at reflux for 2.5 h and was cooled to room temperature. The volatiles were removed in vacuo and water was added. The aqueous solution was extracted with EtOAc (3*) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide (3-bromo-phenyl)-acetic acid ethyl ester (9.30 g) as an oil. 1H NMR (400 MHz, CDCl3) delta7.43 (s, 1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H), 1.24 (t, 3H).
With trifluoroborane diethyl ether; sodium hydrogencarbonate; In dichloromethane; cyclohexane;
Preparation D (3-Bromo-phenyl)-acetic acid tert-butyl ester: To a solution of 3-bromo-phenyl-acetic acid (10 gm, 46.5 mmol) and methylene chloride (47 mL) was added a solution of t-butyl-2,2,2-trichloroacetamidate (20.3 g, 93.0 mmol) and cyclohexane (186 mL) followed by borontrifluoride etherate (0.93 mL, 7.3 mmol). After stirring overnight, solid sodium bicarbonate was added and the reaction then filtered through a pad of silica gel utilizing methylene chloride as solvent. Concentration gave 9.11 g (72%) of a colorless oil. 1H-NMR (CDCl3, delta): 1.41 (s, 9H), 3.46 (s, 2H), 7.1-7.4 (multiplets, 4H).
1-(3-is dimethylaminopropyl)-3-ethylcarbodiimide 4-hydrochloride[ No CAS ]
[ 1878-67-7 ]
[ 117753-07-8 ]
Yield
Reaction Conditions
Operation in experiment
With dmap; dimethyl amine In tetrahydrofuran; dichloromethane
25.a a
a 2-(3-Bromophenyl)-N,N-dimethyl-acetamide Prepared according to the method described in Example 24a) from 1-(3-is dimethylaminopropyl)-3-ethylcarbodiimide 4-hydrochloride (2.15 g), 4-dimethylaminopyridine (3.82 g), a 2M solution of dimethylamine in tetrahydrofuran (10 ml) and a solution of 3-bromophenylacetic acid (2.15 g) in dichloromethane (100 ml). The mixture was stirred overnight at room temperature. The reaction mixture was washed with 2M hydrochloric acid (3*100 ml), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The sub-title compound was obtained as an oil (2.89 g). MS (APCI) 242/244(M+H+) 1H NMR(CDCl3) 7.45-7.35(2H, m); 7.20-7.15(2H, m); 3.65(2H, s); 3.05(3H, s); 2.95(3H, s).
Ethyl (3-bromophenyl)acetate (Compound B1) 100 g (463 mmol) of 3-bromophenylacetic acid was converted into the title compound (yellow oil) using 2 g of conc. H2 SO4 and 500 ml of ethanol by refluxing the reaction for 16 hours. Thereafter, the reaction mixture was cooled to ambient temperature, stirred with solid K2 CO3 for 30 minutes and then filtered. The filtrate was concentrated in vacuo, diluted with Et2 O, washed with 10% aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to give the title compound. PMR (CDCl3): delta 1.26 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).
13.a (a)
(a) 5, and 7-Bromo-2-tetralone m-Bromo-phenylacetic acid (3.4 g, 15.8 mmol) was dissolved in CH2 Cl2 (10 ml) and SOCl2 (1.5 ml) was added and the mixture was refluxed for 1.5 hr. Evaporation of the solvent and excess SOCl2 gave the acid chloride, which was dissolved in CH2 Cl2 (25 ml) and added dropwise during 20 min to a mixture of AlCl3 (9.2 g; 69.0 mmol)) in CH2 Cl2 (200 ml) at about -5° C.
Multi-step reaction with 2 steps
1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C
2: aluminum (III) chloride / dichloromethane / 3 h / -5 - 0 °C
Multi-step reaction with 2 steps
1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C
2: aluminum (III) chloride / dichloromethane / 3 h / -5 - 0 °C
Ethyl (3-bromophenyl)acetate (Compound B) Employing the same general procedure as for the preparation of ethyl (4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of 3-bromophenylacetic acid was converted into the title compound (yellow oil) using 2 g of conc. H2 SO4 and 500 ml of ethanol. PMR (CDCl3): delta 1.26 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).
Ethyl(3-bromophenyl)acetate (Compound B) Employing the same general procedure as for the preparation of ethyl(4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of 3-bromophenylacetic acid was converted into the title compound (yellow oil) using 2 g of conc. H2 SO4 and 500 ml of ethanol. PMR (CDCl3): delta 1.26 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).
Intermediate 50. (3-Bromo-phenyl)-acetic acid tert-butyl ester.[0044] To a solution of 34 (11.2 g, 51.6 mmol) and BoC2O (25 g, 114.5 mmol) in525 mL of £BuOH is added DMAP (1.9 g). The reaction mixture is stirred overnight and checked by TLC till completion. After evaporation of the solvent the product is purified by a short column of silica gel (5-10 cm) up to 10% EtOAc to afford pure (3-bromo-phenyl)- acetic acid ter/-butyl ester 50 as a colorless oil. 1H-NMR (400MHz, CDCl3) delta 7.36(m, 1H),7.34-7.3O (m, 1H),7.15-7.11 (m, 2H)3 3.42 (s, 2H), 1.17 (s, 9H).
With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 4h;
To a stirred solution of compound 0419-1 (2.0 g, 9.3 mmol) in DMF (25 ml) was added (2173) NH4CI (497 mg, 9.3 mmol), HATU (5.3 g, 13.95 mmol), and DIEA (3.6 g, 27.9 mmol) was stirred at rt for 4 h. Then added water, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo , purified by C.C. to give 419-2 (1.5 g, yield: 75.4%) as a white solid.
Example 1 Synthesis of 2-(3-bromophenyl)acetamide 1-Hydroxybenzotriazole (HOBT, 13.82 g, 102.3 mmol), N-ethyldiisopropyl amine (Hunig's base, 13.22 g, 102.3 mmol) and ammonium carbonate (27.0 g, 279.0 mmol) were added to a solution of (3-bromophenyl)acetic acid (20.0 g, 93.0 mmol) in freshly dried and distilled tetrahydrofuran (80 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 5 minutes and then cooled to 0 C and stirred at the same temperature for about 1 hour. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl, 19.61 g, 102.3 mmol) was added at 0 C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 12 hours. The solvent was evaporated under vacuum and water was added. A white solid was obtained which was filtered, washed with water and dried. Yield: 12.69 g. 1H NMR (400 MHz, DMSO-d6): δ 7.52 (brs, 1H, -NH), 7.46 (s, 1H, Ar-H), 7.43-7.40 (m, 2H, Ar-H), 7.25-7.18 (m, 2H, Ar-H), 6.95 (brs, 1H, -NH) and 3.34 (s, 2H, -CH2). Mass Spectrum (m/z, +ve ion mode): 214 [M++1]
1-Hydroxybenzotriazole (HOBT, 13.82 g, 102.3 mmol), N-ethyldiisopropyl amine (Hunig's base, 13.22 g, 102.3 mmol) and ammonium carbonate (27.0 g, 279.0 mmol) were added to a solution of (3-bromophenyl)acetic acid (20.0 g, 93.0 mmol) in freshly dried and distilled tetrahydrofuran (80 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 5 min and then cooled to 0 C. and stirred at the same temperature for about 1 hour. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl, 19.61 g, 102.3 mmol) was added to it at 0 C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 12 hours. The solvent was evaporated under vacuum and water was added to it. A white solid was obtained which was filtered, washed with water and dried. Yield: 12.69 g. 1H NMR (400 MHz, DMSO-d6): δ 7.52 (brs, 1H, -NH), 7.46 (s, 1H, Ar-H), 7.43-7.40 (m, 2H, Ar-H), 7.25-7.18 (m, 2H, Ar-H), 6.95 (brs, 1H, -NH) and 3.34 (s, 2H, -CH2). Mass Spectrum (m/z, +ve ion mode): 214 [M++1]
A solution of LDA in THF/n-heptane/ethylbenzene (1.8M, 23.25 mL, 41.85 mmol) is cooled down to -78C and added a solution of 3-bromophenylacetic acid [3 g, 13.95 mmol, Intermediate (68)] in THF (7 mL) dropwise over 15 minutes. The mixture is stirred for 1 h at -78C and treated dropwise with methyl iodide (6.34 g, 44.64 mmol) over 15 minutes. The reaction mixture is warmed up to room temperature and after stirring overnight, the mixture is quenched with 2N hydrochloric acid and concentrated to remove THF. The residue is diluted with ether, washed twice with 2 N hydrochloric acid (20 mL) and extracted twice with 10% sodium hydroxide (20 mL). The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (50 mL). Combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 2-f3-bromo-phenyl)-propionic acid [3 g, 100%, Intermediate (69)] as a solid, which is used without further purification. LC/MS: 229 (M+H).
84%
To a solution of diisopropylamine (0.97 g, 9.6 mmol) in THF (20 mL) at room temperature was added n-butyl lithium (2.5 N in hexane, 4 mL, 10 mmol) and the resulting solution was stirred at room temperature for 15 minutes. To above solution was added a solution of 3-bromophenylacetic acid (1.0 g, 4.6 mmol) in THF (10 mL) dropwise at room temperature and the stirring was continued for another 15 minutes. Methyl iodide (1.49 g, 10.5 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. Satuated sodium chloride (30 mL) was added and the aqueous phase was adjusted to pH 5 by addition of hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (20 mL×3) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of formic acid and methanol in dichloromethane to afford 2-(3-bromo-phenyl)-propionic acid (890 mg, 84%) as a white solid. MS: m/z 229 (M+H+).
82%
General procedure: Step 1. To a solution of 3-bromophenylacetic acid (1.30 g, 6 mmol) (azeotroped with toluene) in 2 mL of dry toluene was added sodium bis(trimethylsilyl)amide (14 mL of 1N solution in THF, 14 mmol). After stirring at room temperature for 20 min, methyl iodide (0.9 g, 7 mmol) was added dropwise. After 10 min, the reaction was quenched with 2 N HCl to pH = 2, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to dryness. Flash column (SiO2, DCM to DCM/EtOAc = 10:1 to 4:1 to 2:1) gave crude 2-(3-bromophenyl)propanoic acid (1.13 g, 82% yield) as colorless oil.
2-(3-bromophenyl)acetic acid (3g, 13.95mmol) in THF (l5mL) was added to a solution of 2M LDA (22mL, 41.8mmol) at -78 C over a period of 10 mm. The reaction mass was stined for lh at -78 C followed by the drop wise addition of methyl iodide (6.3g, 44.6mmol) over a period of 10 mm. The reaction mass was stined at room temperature for overnight. The reaction mass was quenched with 2N HC1 and concentrated under reduced pressure to remove excess amount of THF. The residue was diluted with ether, washed twice with 2N HC1, extracted the ether layer with 10% NaOH. The combined NaOH layer was acidified with 6N HC1, extracted the compound to ether. The ether layer was washed with water followed by brine, dried and concentrated under reduced pressure to afford the crude compound (2.5g, 78%). LCMS: mlz = 229.1 (M+H)t
3-(3-bromo-benzylidene)-4,7-difluoro-3H-isobenzofuran-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; at 90 - 255℃; for 1.33333h;
Example 3; (a) 3-(3-Bromo-benzylidene)-4, 7-difluoro-3H-isobenzofuran-1-one (H); 3,6 Difluoro phthalic anhydride (G) (6.42g, 34.87mmol), 3-bromo-phenylacetic acid(5.Og, 23.2mmol) and sodium acetate (0.09g, 1.1mmol) were fused together at 250- <n="56"/>255°C for 20 minutes. The reaction was cooled gradually over 1 hour to approximately 900C. Ethanol (25ml_) was added cautiously to the reaction mixture and the resultant precipitate filtered and washed with cold ethanol (1x 15ml). The orange solid was then dried in vacuo. Single peak in LC-MS, (5.29g, 95percent purity) and required no further purification; m/z (LC-MS, ESP), RT=4.76mins (M+NH4) 353.1 355.1.
With 4-methyl-morpholine; 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;
Stage #1: 3-Bromophenylacetic acid With oxalyl dichloride In dichloromethane at 0℃; for 2h; Reflux;
Stage #2: ethene With aluminum (III) chloride In dichloromethane at -10 - -5℃; for 2h;
1 Synthesis of Intermediate 2
100 g (465 mmol) of compound 1 was dissolved in 500 ml of dichloromethane, cooled to 0° C. in ice-salt bath, and added dropwise with 120 g (930 mmol) of oxalyl chloride. After the dropping was finished, the mixture obtained was heated at reflux and reacted for 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated to dryness, and dichloromethane was added and evaporated to dryness again to afford 112 g of intermediate, as a yellow liquid which was used directly in the next step. 210 g (1410 mmol) of aluminum chloride was suspended in 400 ml of dichloromethane, cooled to -10° C. to -5° C., and then added dropwise with a solution of 112 g of the above intermediate in 100 ml of dichloromethane. After the dropping was finished, ethylene gas was introduced into the reaction system for about 2 h keeping the temperature of -10° C. to -5° C. After TLC showed that the reaction was completed, the reaction solution was poured into ice-water mixture and extracted with dichloromethane. The organic phases were combined, washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried, and evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: petroleum ether/ethyl acetate=5/1, v/v) to give a product (85 g) as an orange-red liquid. Yield: 81.7%. LC-MS: 225, 227 [M+1]+, tR=2.153 min.
Stage #1: 3-Bromophenylacetic acid With oxalyl dichloride at 20℃; for 5.08333h; Heating / reflux;
Stage #2: ethene With aluminum (III) chloride In dichloromethane at 0 - 5℃;
4.A
A solution of 3-bromophenylacetic acid (10.4 g, 48.4 mmol) in oxalyl chloride (50 mL, 0.57 mol) was stirred at ambient temperature for 5 min then at reflux for 5 h. The oxalyl chloride was removed in vacuo and the residue was dissolved in anhydrous CH2CL2 (100 ML). This solution was added dropwise to a rapidly stirred, ice-cooled solution of AIDS (23.2 g, 174.2 mmol) in CH2CL2 (500 mL). A stream of ethylene gas was blown into the vortex of the stirred solution during the addition and the reaction temperature was kept at < 5 °C. The reaction mixture was allowed to warm to ambient temperature and then poured onto ice and stirred vigorously. The organic portion was removed and the aqueous layer extracted with CH2C12 (2 x 200 mL). The combined CH2C12 fractions were passed through a 2"pad of silica and concentrated to give a thick, red oil. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane: EtOAc-100: 0 to 75: 25 to provide the title compound as a pale yellow solid. MS : m/z = 226 (M + 1).
Stage #1: 3-Bromophenylacetic acid With oxalyl dichloride at 20℃; for 5.08333h; Heating / reflux;
Stage #2: ethene With aluminum (III) chloride In dichloromethane at 5℃;
11A INTERMEDIATE 11; (+)-7 -AMINO-3 ~4 -DIHYDRO-19H-SPIROFIMIDAZOLIDINE-42 -NAPHTHALENEL-2. 5-DIONE; Step A; 7-Bromo-2-tetralone
A solution of 3-bromophenylacetic acid (10. 4 g, 48.4 mmol) in oxalyl chloride (50 ML, 0.57 mol) was stirred at ambient temperature for 5 min then at reflux for 5 h. The oxalyl chloride was removed in vacuo and the residue was dissolved in anhydrous CH2CL2 (100 mL). This solution was added dropwise to a rapidly stirred, ice-cooled solution of AIDS (23.2 g, 174.2 mmol) in CH2C12 (500 mL). A stream of ethylene gas was blown into the vortex of the stirred solution during the addition and the reaction temperature was kept at < 5 °C. The reaction mixture was allowed to warm to ambient temperature and then poured onto ice and stirred vigorously. The organic portion was removed and the aqueous layer extracted with CH2C12 (2 x 200 mL). The combined CH2C12 fractions were passed through a 2"pad of silica and concentrated to give a thick, red oil. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane : EtOAc-100: 0 to 75: 25 to provide the title compound as a pale yellow solid. MS: MLZ = 226 (M + 1)
(3-Bromophenyl)acetic acid (5.0 g, 23 mmol) was dissolved in tetrahydrofurane (63 mL) and trifluoroacetic anhydride (12 g, 58 mmol) was added at 0 C. After 1 h, tert-butanol (22 g, 302 mmol) was added dropwise and the reaction was stirred at room temperature until TLC showed disappearance of starting material. The reaction was cooled to 0 C and quenched by addition of saturated aqeous bicarbonate solution (100 mL). Ethyl acetate was added and the phases were separated. The organic phase was dried and concentrated in vacuo. The crude was used without further purification in the next step
Stage #1: 3-Bromophenylacetic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.0833333h;
Stage #2: pyrrolidine In N,N-dimethyl-formamide for 18h;
4
INTERMEDIATE 42-(3 -Bromophenyl)- 1 -(pyrrolidin- 1 -vDethanone HBTU (1.24 g, 3.28 mmol) was added to a solution of 3-bromophenylacetic acid(642 mg, 2.99 mmol) and DIPEA (847 mg, 6.57 mmol) in DMF (5 mL). The mixture was stirred for 5 minutes. Pyrrolidine (254 mg, 3.58 mmol) was added and the resulting solution allowed to stand for 18 h. The mixture was partitioned between water and EtOAc (50 mL each). The organic phase was washed with water (20 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 20-100% EtOAc in heptane, and then, on another column, 0-5% MeOH in DCM) to give the title compound {235 mg, 29%) as a brown oil. δH (CDCl3) 7.44 (s, IH), 7.38 (dt, IH), 7.14-7.26 (m, 2H), 3.62 (s, 2H), 3.37-3.56 (m, 4H), 1.77-2.02 (m, 4H). LCMS (ES+) 268 (M+H)+, RT 3.19 minutes.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
General procedure: A mixture 2-amino-4,5-dimethylthiophene-3-carboxamide (340 mg, 2 mmol), 2-(1-naphthalen-1-yl)acetic acid (372 mg, 2 mol), EDC (458 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol), DIEA ( 1.1 mL, 6 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into 100 mL of water then extracted with ethyl acetate (150 mL). The organic layer was washed with saturated NaHCO3 solution (3 x 50 mL), brine (3 x 50 mL), water (3 x 50 mL) respectively. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (30 to 40% ethyl acetate in haxane) to afford compound 1 (277 mg, 41%).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: To a round-bottom flask (500 mL) that contained a solution of aryl sulfonamide (6 mmol), 4-dimethyaminopyridine (DMAP, 13 mmol), and 1-[3-(dimethyamino)-propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 13 mmol) in CH2Cl2 (150 mL) was added the synthesized phenylacetic acid (6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h, then cooled to 5 C, and acidified to pH 1 with addition of HCl aqueous solution (10%), which was followed by extraction with CH2Cl2/MeOH (9:1, 3 × 100 mL). The combined organic layers were washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to silica gel chromatography or crystallization if necessary to afford the compounds (20-44) (Scheme 2).
Step A: Ethyl 2-(3-bromophenyl acetate (35i-b) 3-Bromophenylacetic acid, 35i-a, (50g, 0.23mol) was dissolved in ethanol (250 mL) and sulfuric acid was added drop-wise. The mixture was heated to reflux and stirred overnight. The solution was adjusted to about a pH of 7-8 with sodium hydroxide solution and concentrated in vacuo. The water phase was extracted with ethyl atetate (3 x 150 mL) and the combined organics was washed with brine (50 mL) and dried, concentrated to give the compound, 35i-b, (52.6g, 93%) as colorless oil. NMR (300 MHz, CDCI3) delta 1.24-1.29 (m, 3H), 3.58 (s, 2H), 4.1 1-4.19 (m, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 2H). LC-MS (M+H)+ 243, 245.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;
General procedure for the synthesis of 2-phenyl-N-(4-phenylthiazol-2-yl) acetamide derivatives 3a-3l and 4a-4l
General procedure: For the synthesis of compounds 3a-3h, 3j, 3k, 4a-4h, 4j, 4k, a mixtureof corresponding acids (1 mmol), 4-phenylthiazol-2-ylamine derivatives (2a or 2b, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 1.5 mmol), 1-hydroxybenzotrizole (HOBt, 0.05 mmol) in CH2Cl2 (20-30mL) was stirred at room temperature for 24 h. After that, the solvent was removed in vacuo to afford a residue, which was extracted with EtOAc (3 ×20mL). The combined organic phases were dried with anhydrous Na2SO4. Removal of all the solvent in vacuo resulted in a residue, which was purified with recrystallization to give target products.
With lithium hydroxide; In tetrahydrofuran; water; at 20℃; for 1h;
Under room temperature, will <strong>[14062-30-7]ethyl 3-bromophenylacetate</strong> (5.0 g, 20.6 mmol) and LiOH (1.0 g, 41.8 mmol) added THF (30 ml) and water (20 ml) in the mixed solution. Under room temperature, the resultant reaction mixture of 1 hour. Using 2N pH=2. HCl solution to adjust the The resulting mixture is extracted with ethyl acetate. The resulting organic phase is concentrated to obtain 4.1 g of white solid.
Stage #1: 1-(3-Bromophenyl)ethanone With 4-methyl-morpholine; sulfur for 14h; Reflux;
Stage #2: With sulfuric acid; acetic acid In water at 20 - 30℃; for 6h; Reflux;
1.1 first stepPreparation of 3-bromo-phenylacetic acid (2)
In 1000ml three-necked flask of sublimed sulfur were added 24g (0.75mol), 100g3- bromoacetophenone (0.5mol) and 65.4g (0.75mol) morpholine was stirred at reflux for 14 hours. Cooling to 20 ~ 30 , stirring joined by glacial acetic acid 260ml, 75ml and 52ml distilled water mixed with concentrated sulfuric acid solution dubbed refluxing was continued for 6 hours. The reaction mixture was poured into ice water, stirring to brown solid precipitated was filtered. The solid was dissolved 300ml20% aqueous sodium hydroxide solution and filtered. The filtrate was placed in an ice bath, 2mol / L of hydrochloric acid to adjust pH = 1 ~ 2, crystallization, filtration, 60 dried to give 99.2g of yellow solid 2, a yield of 92.3%.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: An oven-dried 50 mL round-bottom flask containing a magnetic stirrer bar was sealed with a septum, charged with Ar and tared on a balance. KH (~0.5 g, 30% mineral oil dispersion) was then added to the flask and the mineral oil removed by trituration under Ar with pet. spirit (2 x 30 mL) using a syringe. The flask containing dry KH was purged with Ar and reweighed to obtain an accurate mass of KH. Dry THF (10 mL) was added to the flask containing KH (0.15 g, 3.7 mmol, under Ar) and the mixture cooled to 0 oC. 3,5-Dimethyl-1H-pyrrole-2-carbaldehyde 5 (0.23 g, 1.9 mmol) was dissolved in dry THF (5 mL) under Ar and added dropwise to the stirring KH solution (Caution - flask requires outlet needle to release evolving H2 gas). After complete addition the mixture was stirred for a further 5 minutes at 0 oC. The phenylacetic acid derivative (1.9 mmoles) was added to a separate dry 50 mL round-bottom flask under Ar along with HBTU (0.71 g, 1.9 mmoles) and dry CH2Cl2 (10 mL). DIPEA (0.65 mL, 3.7 mmoles) was added dropwise to the stirring solution and upon complete addition the mixture was stirred for a further 5 minutes or until the HBTU was completely dissolved. The HBTU solution was then cooled to 0 oC and added in a single portion to the K+ pyrrolate salt solution at 0 oC and the combined mixture allowed to warm slowly to room temperature. A dark red colour observed in each reaction indicated formation of the desired 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one. The reaction was quenched after ~ 2 h with ice-cold water (100 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was washed with 1 M HCl (2 x 50 mL), saturated NaHCO3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography using a gradient from 100% pet. spirit to 1:9 acetone:pet. spirit to afford the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one as a deep red solid.
tert-butyl 3-(2-(3-bromophenyl)acetamido)-5-methyl-1H-pyrazole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 12h;
To a solution of 2-(3-bromophenyl)acetic acid (0.5g, 2.32mmol) in DCM (20mL) was added EDCI (0.88g, 0.4.65mmol) at 0 C followed by DIPEA (1.l2mL, 6.97mmol) and finally added tert-butyl 3-amino-5-methyl- 1 H-pyrazole- 1 -carboxylate (0.4g, 2.O9mmol). The reaction mass was stined for 12h at room temperature. The reaction mixture was quenched with ice-water and diluted with DCM. The aqueous layer was separated and extracted with ethyl acetate (2x25mL). The combined organic phase was washed with brine, dried over Na2504, filtered and concentrated under reduced pressure and purified by eluting with 20% ethyl acetate-hexane in combiflash to afford the title compound (0.3g, 60%). LCMS: mlz = 395.9 (M+H).
Stage #1: 3-Bromophenylacetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h;
Stage #2: homoalylic alcohol With N-ethyl-N,N-diisopropylamine In dichloromethane for 12h;
Scheme S3. Preparation of 3-butenyl α-arylacetates.
General procedure: A round bottom flask which was charged with aryl acetic acid (5 mmol, 1.0 equiv) in drydichloromethane (40 mL) was added EDCI (1.05g, 5.5 mmol, 1.1 equiv) and HOBT (743mg,5.5 mmol, 1.1 equiv) at rt. After being stirred for 30 min at rt, DIEPA (2.6 mL, 15 mmol, 3equiv) and 3-butene-1-ol (432 mg, 6.0 mmol, 1.2 equiv) was added to the mixture. The reactionwas stirred for 12 h. The reaction was quenched by 1N aq. HCl and extracted by AcOEt. Theextract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give aresidue. The residue was purified by column chromatography (SiO2, hexane : AcOEt = 9 : 1) togive α-arylacetate S1.
2-(3-bromophenyl)-N-[2-(trifluoromethoxy)phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound.
With copper(II) acetate monohydrate; sulfur; sodium hydroxide; In dimethyl sulfoxide; at 130.0℃; for 24.0h;Sealed tube; Inert atmosphere;
General procedure: A mixture of o-iodoaniline (0.5 mmol, 1 equiv), arylacetic acid (0.6 mmol), elemental sulfur (1.5mmol), Cu(OAc)2·H2O (20 mmol%), and NaOH (1.0 mmol) in DMSO (3 mL) was put into a sealed pressure vessel (25 mL) containing a magnetic stirring bar. The tube was purged with nitrogen three times, and then capped and stirred in a preheated oil bath at 130 C for 24 h. The reaction mixture then cooled to room temperature and extracted with ethyl acetate (3x10 mL), the organic layer was washed with saturated NaCl (2x10 mL), dried over anhydrous Na2SO4, evaporated under vacumm and then purified by silica gel column chromatography by using petroleum ether and ethyl acetate (PE:EA=200:1) as eluent.
ethyl 2-[[2-(3-bromophenyl)acetyl]amino]-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 15℃; for 16h;
To a solution of 2-(3-bromophenyl)acetic acid (5.00 g, 23.3 mmol, CAS 1878-67- 7), HATU (11.5 g, 30.2 mmol) and diisopropylethylamine (9.01 g, 69.8 mmol) in DCM (100 mL) was added ethyl 2-amino-2-methyl-propanoate (4.29 g, 25.6 mmol, HCl salt). The reaction mixture was stirred at 15 C for 16 hrs. On completion, the reaction mixture was washed with 1N HCl solution until pH = 6. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1) to give the title compound (3.00 g, 39% yield) as a white solid. LCMS: (ES+) m/z (M)+= 328.0, tR =0.746.
Multi-step reaction with 3 steps
1.1: hydrogenchloride / 5.08 h / 0 - 20 °C
2.1: sodium hexamethyldisilazane / tetrahydrofuran / 0.33 h / -78 °C
2.2: 3.5 h / -78 °C
3.1: lithium hydroxide; water / methanol / 20 °C
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;
1 Embodiment 1
Taking a 100 ml round-bottom flask, the DCC (1.0320 g, 5 mmol), DMAP (0.1527 g, 1 . 25 mmol) and 4 - bromophenylacetic acid (0.5376 g, 2.5 mmol) by adding 10 ml of dichloromethane in the drying of, 20 °C stirring to dissolve all. The 3 - bromophenylacetic acid (0.5376 g, 2.5 mmol) to dissolve to 20 ml in dry dichloromethane, then constant voltage used in the dropping funnel slowly to the above solution. Stirring 24 h, turns on lathe does, then column chromatographic separation (step elution, first with petroleum ether elution, then volume ratio of ethyl acetate: petroleum ether=1:10) so as to obtain the target compound.
4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl 2-(3-bromophenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: o-Tolylacetic acid (0.59 g; 1.0 equiv; 3.77 mmol) and47.0 mg 4-DMAP (10 mol %; 0.38 mmol) were added to a100-mL round flask containing 1 g compound c (3.77 mmol) and stirred in an ice bath for 5 min after the addition of 20 mL methylene chloride. Afterward, 0.80 g DCC (1.0 equiv; 3.77 mmol) was added into the mixture and allowed to react for 3 h at room temperature, until the starting materials (TLC analysis) began to disappear. The resulting DHU was filtered under reduced pressure. The filtrate was extracted using 0.5 M HCl and a saturated solution of NaHCO3 in order. The solvent was removed under reduced pressure after dehydration using anhydrousMgSO4. The purified solid was obtained by recrystallization from ethanol as a light yellow solid. Synthesis of compounds 39-57 is shown in Scheme 1.
2-(3-bromophenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: 3-Bromophenylacetic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: 3-(trifluoromethyl)-4-methylaniline In N,N-dimethyl-formamide for 8h;
1.6.1. General procedure for the synthesis of compounds 23 and 26a-b
General procedure: To a mixture of compounds 22 or 25ab (4.6 mmol, 1.0 eq), dicyclohexylcarbodiimide (DCC) (1.2 eq) and 1-hydroxybenzotriazole (HOBT) (1.2 eq) in anhydrous DMF (10 mL) was stirred at room temperature for 1 h followed by adding 4-methyl-3-(trifluoromethyl)aniline 1c (1.2 eq), and continued to be stirred for 8 h. The reaction solution was added 30 mL of deionized water and extracted with ethyl acetate (30 mL×4). The combined organic layer was washed with 1M HCl solution (15 mL), brine (15 mL) and dried over Na2SO4. The solvent was concentrated in vacuo and purified by column chromatography (PE: EtOAc = 50:1 ~ 5:1) to afford compounds 23 and 26a-b.
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